Low coherence interferometry for detecting and characterizing plaques

ABSTRACT

A method for determining a characteristic of tissue in a biological sample comprising: directing light at the biological sample at a first depth and receiving that light reflected from the biological; directing the light at a reflecting device and receiving that light reflected from the reflecting device. The method also includes: interfering the light reflected from the biological sample and the light reflected from the reflecting device; detecting light resulting from the interfering; and determining a first phase associated with the light resulting from the interfering based on the first depth. The method further includes: varying an effective light path length to define a second depth; determining a second phase associated with the light resulting from the interfering based on the second depth; and determining the characteristic of the biological sample from the first phase and the second phase.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part application of U.S. Ser. No. 10/845,849,filed May 14, 2004 the contents of which are incorporated by referenceherein in their entirety.

BACKGROUND

The invention concerns a low coherence interferometric (LCI) method fordetecting plaques. For example, a method and apparatus for the analysisand detection of atheromas and/or atherosclerotic plaques in arterialwalls. More particularly, in one embodiment, a methodology and systemfor detecting and evaluating vulnerable atherosclerotic plaques in ablood vessel. Further, measurement of the interface between the plaqueand lipid pool between the plaque and the artery and measurement thethickness of the plaque with a high accuracy. An application area ofinterest is that of the diagnosis and management of cardiovasculardiseases (CVD).

Coronary Heart Disease (CHD) accounts for approximately fifty percent ofthe death toll attributed to CVD. Despite major advances in thetreatment of coronary heart disease patients, a large number of victimsof CHD who are apparently healthy die suddenly without prior symptoms.Available screening and diagnostic methods are insufficient to identifythe victims before the catastrophic event occurs. The recognition of therole of the vulnerable plaque has opened new avenues of opportunity inthe field of cardiovascular medicine. Vulnerable plaques have beendefined as any atherosclerotic plaque with high likelihood of thromboticcomplications and rapid progression. Researchers have found that manypeople who experience heart attacks do not have arteries that have beenseverely narrowed by plaque. In fact, vulnerable plaque may be buriedinside the arterial wall. It has also been found that in theseindividuals, that vulnerable plaque manifested itself as more than justdebris clogging an artery, but that it was filled with different celltypes that induce blood clotting. One particularly lethal type ofvulnerable plaque is generated through an inflammation process, leadingto the formation of a large lipid core inside the artery wall, coveredby a thin fibrous cap. When this thin covering over the plaque cracksand bleeds, it spills the contents of the vulnerable plaque into thebloodstream, creating clots large enough to block the artery.

Therefore, there is considerable interest in the identification ofplaques prior to the occurrence of thrombosis. Early detection wouldenhance therapies, while leading to trials of novel preventive measures.Multiple new technologies to improve characterization of plaque inpatients are under development. These techniques seek to identify thehistologic features, of plaques suspected to represent vulnerability,and provide additional information that heretofore has not beenavailable. Data on structure, composition, deformability,pathophysiology, metabolism, temperature, and the like will enhancecharacterization. The additional information is key to the accuratedetection, characterization and management of vulnerable plaque, withpositive outcome for the patients.

Peripheral Vascular Disease (PVD) affects 8 to 12 million Americans andis associated with significant disability and mortality. PVD is acondition in which the arteries that carry blood to the arms or legsbecome narrowed or clogged. This narrowing or clogging interferes withthe normal flow of blood, sometimes causing pain but often exhibiting nosymptoms at all. The most common cause of PVD is atherosclerosis, agradual process in which cholesterol and scar tissue build up, forming asubstance called “plaque” that clogs the blood vessels. In some cases,PVD may be caused by blood clots that lodge in the arteries and restrictblood flow. In extreme cases, untreated PVD can lead to gangrene, aserious condition that may require amputation of a leg, foot or toes.

In general, atheromatous or atherosclerotic plaques characteristicallycomprise a fibrous cap surrounding a central core of extracellularlipids and debris located in the central portion of the thickened vesselintima, which is known as the “atheroma”. On the luminal side of thelipid core, the fibrous cap is comprised mainly of connective tissues,typically a dense, fibrous, extracellular matrix made up of collagens,elastins, proteoglycans and other extracellular matrix materials. In thecase of arterial plaques the chronically stenotic plaque in whichcalcified material builds up in the artery to cause occlusion asdiscussed above may readily be distinguished from the rupture-pronevulnerable plaque, which consists of a thin fibrous cap and a largelipid core in the wall of the artery. The stenotic plaque is easilydetected with MRI, ultrasound, and other diagnostic techniques. Oncedetected, it is opened up using a stent within a catheter.

With an active atheromatous or atherosclerotic plaque, at the edges ofthe fibrous cap overlying the lipid core comprises the shoulder regionand is enriched with macrophages. The macrophages continuallyphagocytose oxidized LDL through scavenger receptors, which have a highligand specificity for oxidized LDL. Continuous phagocytosis results inthe formation of foam cells, a hallmark of the atherosclerotic plaque.Foam cells, together with the binding of extracellular lipids tocollagen fibers and proteoglycans, play an important role in theformation and growth of the lipid-rich atheroma.

Examination of atheromatous/atherosclerotic plaques has revealedsubstantial variations in the thickness of fibrous caps, the size of theatheromas, the extent of dystrophic calcification, and the relativecontribution of major cell types. Atheromatous plaques include asignificant population of inflammatory cells, such as monocytes ormacrophages and T lymphocytes. The emigration of monocytes into thearterial wall, and their subsequent differentiation into macrophages andultimately foam cells, remains one of the earliest steps in plaqueformation. Once there, these cells play a critical role in secretingsubstances that further contribute to atherosclerosis.

The causative agent of acute coronary syndrome is fissure, erosion orrupture of a specific kind of atheromatous plaque known as a “vulnerableplaque.” It has been determined that vulnerable plaques are responsiblefor the majority of heart attacks, strokes, and cases of sudden death. Avulnerable plaque is structurally and functionally distinguishable froma stable atheromatous plaque. For example, a vulnerable plaque ischaracterized by an abundance of inflammatory cells (e.g., macrophagesand/or T cells), a large lipid pool, and a thin fibrous cap. Pathologicstudies have also provided a further understanding of why vulnerableplaques have a higher propensity for rupture than other atheromatousplaques. The thickness and integrity of the fibrous cap overlying thelipid-rich core is a principal factor in the stability of the plaque.Generally, atheromatous plaques prone to rupture can be characterized ashaving thinner fibrous areas, increased numbers of inflammatory cells(e.g., macrophages and T cells), and a relative paucity of vascularsmooth muscle cells. Vascular smooth muscle cells are the major sourceof extra cellular matrix production, and therefore, the absence ofvascular smooth muscle cells from an atheromatous plaque contributes tothe lack of density in its fibrous cap.

While the fibrous tissue within the cap provides structural integrity tothe plaque, the interior of the atheroma is soft, weak and highlythrombogenic. It is rich in extracellular lipids and substantiallydevoid of living cells, but bordered by a rim of lipid-ladenmacrophages. The lipid core is a highly thrombogenic composition, richin tissue factor, which is one of the most potent procoagulants known.The lesional macrophages and foam cells produce a variety ofprocoagulant substances, including tissue factor. The fibrous cap is theonly barrier separating the circulation from the lipid core and itspowerful coagulation system designed to generate thrombus. Essentially,the rapid release of procoagulants into the blood stream at the site ofrupture forms an occlusive clot, inducing acute coronary syndrome. Thus,the thinner the fibrous cap, the greater the instability of thethrombogenic lipid core and the greater the propensity for rupture andthrombosis. Generally, it has been determined that the criticalthickness of the cap is of the order of 70 microns.

Common methods of plaque detection include angiography and angioscopy.Except in rare circumstances, angiography gives almost no informationabout the characteristics of plaque components. However, angiography isonly sensitive enough to detect hemodynamically significant lesions(>70% stenosis), which account for approximately 33% of acute coronarysyndrome cases. Angioscopy is a technique based on fiber-optictransmission of visible light that provides a small field of view withrelatively low resolution for visualization of interior surfaces ofplaque and thrombus. Because angioscopic visualization is limited to thesurface of the plaque, it is generally insufficient for use in detectingactively forming atheromatous plaques and/or determining vulnerableplaques.

Several methods are being investigated for their ability to identifyatheromatous plaques. One such method, intravascular ultrasound (“IVUS”)uses miniaturized crystals incorporated at catheter tips and providesreal-time, cross-sectional and longitudinal, high-resolution images ofthe arterial wall with three-dimensional reconstruction capabilities.IVUS can detect thin caps and distinguish regions of intermediatedensity (e.g., intima that is rich in smooth muscle cells and fibroustissue) from echolucent regions, but current technology does notdetermine which echolucent regions are composed of cholesterol poolsrather than thrombosis, hemorrhage, or some combination thereof.Moreover, the spatial resolution (i.e., approximately 100 μm) does notdistinguish the moderately thinned cap from the high risk cap (i.e.,approximately 25-75 μm) and large dense calcium deposits produceacoustic echoes which “shadow” so that deeper plaque is not imaged.

Intravascular thermography is based on the premise that atheromatousplaques with dense macrophage infiltration give off more heat thannon-inflamed plaque. The temperature of the plaque is inverselycorrelated to cap thickness. However, thermography may not provideinformation about eroded but non-inflamed lesions, vulnerable orotherwise, having a propensity to rupture.

Raman spectroscopy utilizes Raman effect: a basic principle in photonicspectroscopy named after its inventor. Raman effect arises when anincident light excites molecules in a sample, which subsequently scatterthe light. While most of this scattered light is at the same wavelengthas the incident light, some is scattered at a different wavelength. Thisshift in the wavelength of the scattered light is called Raman shift.The amount of the wavelength shift and intensity depends on the size,shape, and strength of the molecule. Each molecule has its own distinct“fingerprint” Raman shift. Raman spectroscopy is a very sensitivetechnique and is capable of reporting an accurate measurement ofchemical compounds. Conceivably, the ratio of lipid to proteins, such ascollagen and elastin, might help detect vulnerable plaques with largelipid pools. However, it is unlikely that actively forming and/orvulnerable plaques will be reliably differentiated from stable plaquesbased solely on this ratio.

Radiation-based methods for detection of diseased tissue are also knownin the art. Some devices include an ion-implanted silicon radiationdetector located at the tip of a probe with a preamplifier containedwithin the body of the probe, and connected to the detector as well asexternal electronics for signal handling. Another device providesradio-pharmaceuticals for detecting diseased tissue, such as a canceroustumor, followed by the use of a probe with one or more ion-implantedsilicon detectors at its tip to locate the radio labeled diseasedtissue; the detector is preferentially responsive to beta emissions.

Optical coherence tomography (“OCT”) measures the intensity of reflectednear-infrared light from tissue. OCT is an application of to form 3Dimages. OCT provides images with high resolutions that are approximately10 to 20 times higher than that of IVUS, which facilitates detection ofa thin fibrous cap. Advantageously, while other methodologies mayexhibit the capability to detect the presence of lipids within thevessel wall, OCT techniques have been shown to exhibit the spatialresolution sufficient for resolving the parameters directly responsiblefor plaque ruptures. Unfortunately, OCT is an imaging technique and, asa result, is computationally intensive and very time consuming. Theresulting images from OCT require skilled interpretation for thedetection of vulnerable plaques.

Low Coherence Interferometry (LCI) is an optical technique that allowsfor accurate, analysis of optical interfaces, and is very adaptable tothe analysis of the scattering properties of heterogeneous optical mediasuch as layered biological tissue. Furthermore, the interface betweentwo regions in biological tissues exhibiting different opticalcharacteristics is characterized by change in scattering, absorption,and refractive index characteristics. Of particular interest, aresensitive methods to measure the important features of the signal at thediscontinuity e.g., such as between a fibrous cap and lipid pool. InLCI, light from a broad bandwidth light source is first split intosample and reference light beams which are both retro-reflected, from atargeted region of the sample and from a reference mirror, respectively,and are subsequently recombined to generate an interference signalhaving maxima at the locations of constructive interference and minimaat the locations of destructive interference. The interference signal isthen employed to evaluate the characteristics of the sample. LCIexhibits very high resolution as the detectable interference occurs onlyif the optical path difference between them is less than the coherencelength of the source. LCI can be used in the detection andcharacterization of blockage sites in peripheral arteries. The LCIinterferometer can be made out of optical fibers, and therefore can beeasily integrated with catheters used by interventional radiologists toopen blood vessels. Unfortunately, current LCI techniques, such as OCT,rely on amplitude measurements of the interferences signal and may lackthe high resolution required for accurate detection and characterizationof vulnerable plaques.

The term “biological sample” denotes a body fluid or tissue of a livingorganism. Biological samples are generally optically heterogeneous, thatis, they contain a plurality of scattering centers scattering irradiatedlight. In the case of biological tissue, especially skin tissue, thecell walls and other intra-tissue components form the scatteringcenters.

In spite of these endeavors, attempts to make available an effectivesensor for practical operation to detect vulnerable plaque have thusfar, proved inadequate. What is needed in the art is a new approach forLCI-based plaque detection and characterization based on the measurementof the phase of the interferometric signal to facilitate accuratedetection and characterization of atheromatic/atherosclerotic plaquesand particularly vulnerable plaques.

BRIEF SUMMARY

The above discussed and other drawbacks and deficiencies of the priorart are overcome or alleviated by the measurement system and methodologydisclosed herein. Disclosed herein in an exemplary embodiment is amethod for determining a characteristic of tissue in a biologicalsample, the method comprising: directing broadband light by means of asensing light path at the biological sample at a first depth defined byeffective light path lengths of the sensing light path and a referencelight path; receiving the broadband light reflected from the biologicalsample by means of the sensing light path; directing the broadband lightby means of the reference light path at a reflecting device; andreceiving the broadband light reflected from the reflecting device bymeans of the reference light path. The method also includes: interferingthe broadband light reflected from the biological sample and thebroadband light reflected from the reflecting device; detectingbroadband light resulting from the interfering of the broadband lightreflected from the biological sample and the broadband light reflectedfrom the reflecting device; and determining a first phase associatedwith the broadband light resulting from the interfering of the broadbandlight reflected from the biological sample and the broadband lightreflected from the reflecting device based on the first depth. Themethod further includes: varying the effective light path lengths of atleast one of the reference light path and the sensing light path todefine a second depth; determining a second phase associated with thebroadband light resulting from the interfering of the broadband lightreflected from the biological sample and the broadband light reflectedfrom the reflecting device based on the second depth; and determiningthe characteristic of the biological sample from the first phase and thesecond phase.

Also disclosed herein in an exemplary embodiment is a system fordetermining a characteristic of tissue in a biological sample, thesystem comprising: a broadband light source for providing a broadbandlight; a sensing light path receptive to the broadband light from thebroadband light source, the sensing light path configured to direct thebroadband light at the biological sample and to receive the broadbandlight reflected from the biological sample; a reflecting device; and areference light path receptive to the broadband light from the broadbandlight source, the reference light path configured to direct thebroadband light at the reflecting device and to receive the broadbandlight reflected from the reflecting device, the reference light pathcoupled with the sensing light path to facilitate interference of thebroadband light reflected from the biological sample and the broadbandlight reflected from the fixed reflecting device. The system alsoincludes a detector receptive to the broadband light resulting frominterference of the broadband light reflected from the biological sampleand the broadband light reflected from the reflecting device; and ameans for varying effective light path lengths of at least one of thereference light path and the sensing light path. The system furtherincludes a processor configured to; (1) determine a first phaseassociated with the broadband light resulting from the interfering ofthe broadband light reflected from the biological sample and thebroadband light reflected from the reflecting device based on a firstdepth, the first depth defined by the effective light path lengths ofthe sensing light path and a reference light path, (2) determine asecond phase associated with the broadband light resulting from theinterfering of broadband light reflected from the biological sample andthe broadband light reflected from the reflecting device based on asecond depth, the second depth defined by effective light path lengthsof the sensing light path and a reference light path, and (3) determinethe characteristic of the biological sample from the first phase and thesecond phase.

Further disclosed herein in yet another exemplary embodiment is a systemfor determining a characteristic of tissue in a biological sample, thesystem comprising: means for directing broadband light by means of asensing light path at the biological sample at a first depth defined byeffective light path lengths of the sensing light path and a referencelight path; means for receiving the broadband light reflected from thebiological sample by means of the sensing light path; means fordirecting the broadband light by means of the reference light path at areflecting device; and means for receiving the broadband light reflectedfrom the reflecting device by means of the reference light path. Thesystem also includes: means for interfering the broadband lightreflected from the biological sample and the broadband light reflectedfrom the reflecting device; means for detecting broadband lightresulting from the interfering of the broadband light reflected from thebiological sample and the broadband light reflected from the reflectingdevice; and means for determining a first phase associated with thebroadband light resulting from the interfering of the broadband lightreflected from the biological sample and the broadband light reflectedfrom the reflecting device based on the first depth. The system furtherincludes: means for varying the effective light path lengths of at leastone of the reference light path and the sensing light path to define asecond depth; means for determining a second phase associated with thebroadband light resulting from the interfering of the broadband lightreflected from the biological sample and the broadband light reflectedfrom the reflecting device based on the second depth; and means fordetermining the characteristic of the biological sample from the firstphase and the second phase.

Also disclosed herein in yet another exemplary embodiment is a storagemedium encoded with a machine-readable computer program code fordetermining a characteristic of tissue in a biological sample, includinginstructions for causing a computer to implement the abovementionedmethod.

Further in yet another exemplary embodiment there is disclosed acomputer data signal embodied in a computer readable format fordetermining a characteristic of tissue in a biological sample, thecomputer data signal including instructions for causing a computer toimplement the abovementioned method.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other features and advantages of the present invention may bebest understood by reading the accompanying detailed description of theexemplary embodiments while referring to the accompanying figureswherein like elements are numbered alike in the several figures inwhich:

FIG. 1 is a basic all-fiber low-coherence interferometer (LCI);

FIG. 2 depicts an illustrative exponential dependence on z for ascattering material such as human tissue as a sample;

FIG. 3A depicts a plot of an illustrative envelope function G(Δl;

FIG. 3B depicts a plot of an illustrative interference signal G(Δl)cosφ_(s);

FIG. 4A depicts an illustrative exponential decay for a homogeneousscattering sample with space between the probe tip and the sample;

FIG. 4B depicts an illustrative exponential decay for a homogeneousscattering sample with the probe tip immersed in the sample;

FIG. 5A depicts an example of an LCI profile based on observations ofthe walls of arteries through flowing blood;

FIG. 5B depicts a representation of an LCI signal for a calcified plaqueon an arterial wall with a lipid pool between the plaque and thearterial wall, looking through blood;

FIG. 6 depicts a system for detecting and characterizing vulnerableplaque in accordance with an exemplary embodiment;

FIG. 7 depicts another system for detecting and characterizingvulnerable plaque in accordance with another exemplary embodiment;

FIG. 8A depicts a range of unambiguous measurement for a periodicinterference signal;

FIG. 8B depicts a plot of the interference signal for a single ramp;

FIG. 9A depicts the values of Δl for a periodic ramp for a=5λ_(o) andb=0.5a;

FIG. 9B depicts the envelope function as a function of time for theparticular G(t) for a=5λ_(o) and b=0.5a;

FIG. 9C depicts the output current or interference signal for a=5λ₅ andb=0.5a;

FIG. 10A depict the values of Δl for a periodic ramp for a=λ_(o) andb=0.5a;

FIG. 10B depicts the envelope function as a function of time for theparticular G(t) for a=λ_(o) and b=0.5a;

FIG. 10C depicts the output current or interference signal for a=λ_(o)and b=0.5a;

FIG. 11 depicts an a simplified block depicting a detection schemeemploying ramp modulation;

FIG. 12A shows a balanced interferometric signal resultant fromsinusoidal modulation depicting a heavy portion oscillating at thefrequency f over the peak;

FIG. 12B shows an unbalanced interferometric signal, and a shiftedmodulation pattern;

FIG. 13 depicts an implementation of a sinusoidal modulation or homodynedetection scheme;

FIG. 14 depicts a fiber probe and guidewire in accordance with anexemplary embodiment;

FIG. 15A depicts a probe tip in accordance with an exemplary embodiment;

FIG. 15B depicts a probe tip in accordance with another exemplaryembodiment;

FIG. 16 depicts a minimum configuration interferometer system inaccordance with an exemplary embodiment of the invention;

FIG. 17 depicts a configuration of an interferometer system inaccordance with an exemplary embodiment of the invention;

FIG. 18 depicts an illustration of a splitter-modulator module inaccordance with an exemplary embodiment;

FIG. 19A depicts a process for fabricating the splitter-modulator modulein accordance with an exemplary embodiment;

FIG. 19B depicts a process of fabricating the splitter-modulator modulein accordance with an exemplary embodiment;

FIG. 19C depicts a process of fabricating the splitter-modulator modulein accordance with an exemplary embodiment;

FIG. 20 depicts an adaptation of the interferometer system of FIG. 16/17with a calibration strip;

FIG. 21A depicts an interface for extension modules in accordance withanother exemplary embodiment of the invention;

FIG. 21B depicts an interface for extension in accordance with anotherexemplary embodiment of the invention;

FIG. 21C depicts another interface for extension in accordance with yetanother exemplary embodiment of the invention;

FIG. 22 depicts a miniaturized, handheld LCI system in accordance withan exemplary embodiment;

FIG. 23 depicts a miniaturized, handheld LCI system in accordance withan exemplary embodiment; and

FIG. 24 depicts a miniaturized, handheld LCI system in accordance withan exemplary embodiment.

DETAILED DESCRIPTION OF AN EXEMPLARY EMBODIMENT

Disclosed herein, in several exemplary embodiments are high-sensitivitylow coherence interferometric (LCI) systems (instruments) for opticalmetrology, for use in a variety of sensing and monitoring applications,including, but not limited to, trace chemical sensing, opticalproperties and changes thereof, medical sensing such as detecting andcharacterizing vulnerable plaques and others. In an exemplaryembodiment, the instrument is miniaturized, using integrated opticscomponents such as waveguides, splitters and modulators on a singlesubstrate such as, but not limited to, a LiNbO₃ (Lithium Niobate) chip.The exemplary embodiments may also involve the use of a “circulator”type of optical component, including of a polarizing beam splitter andquarterwave plate, which can be combined with the light source anddetector into a miniature module that prevents optical feedback into thelight source while doubling the detected light. Alternatively, insteadof the polarizing beam splitter and quarter wave plate, one or moreisolators and a waveguide coupler or devices using Faraday rotation inmagneto-optic films may be employed in a similar module to accomplishthe same purpose. Disclosed herein in the exemplary embodiments aremultiple methodologies and associated systems employed to deriveinformation from the magnitude and/or phase of an interferometric signalfor detecting and characterizing vulnerable plaques.

It will be appreciated that while the exemplary embodiments describedherein are suitable for the detection and characterization of vulnerableplaques, the embodiments may further be applicable to detection of otherlesions such as skin cancer and lesions lining the walls of internalorgans such as the esophagus, colon, etc. It may be further appreciatedthat the methods discussed herein generally permit an absolutemeasurement of the characteristics of atheromatic/atheroscleroticplaque, such as its thickness, as well as relative measurement from agiven baseline for a given medium. Therefore, for relative measurements,calibration to establish a baseline may be required. For instance, forone exemplary embodiment, a calibration strip is employed to facilitatecalibration. Other methodologies, such as using a sample of known indexof refraction may also be employed.

It should also be noted that the light wavelengths discussed below forsuch methods may be in the range of about 300 to about several thousandnanometers (nm), that is, in the spectral range from near ultraviolet tonear infrared light. In an exemplary embodiment, for the sake ofillustration, a wavelength of about 1300 nm is employed. The term“light” as used herein is not to be construed as being limited orrestricted to the visible spectral range. However, it should beappreciated that LCI can occur in any interferometric system using broadfrequency or wavelength bandwidth.

It will also be noted that for a homogeneously scattering medium forwhich a specific property such as the refractive index is to bemeasured, it is sufficient to probe at a single depth, as the desiredinformation can be obtained from the phase of the interferometricsignal, presumed to be independent of the amplitude. In this case, aninstrument as described herein can be configured for measurement at asingle depth. However, in an exemplary embodiment, to probe forinhomogeneities (local changes of absorption, reflection, or refractiveindex), as would be expected for the several layers of aatheromatic/atherosclerotic plaque the instrument may be configured tomeasure both the amplitude and the phase of the interferometric signalas functions of depth. Described herein in an exemplary embodiment is asystem configured to probe at variable depths and for general imagingpurposes, while later embodiments may be employed for measurement atfixed depth. For example, probes at various depths may be employed toidentify the various layers and the respective thickness for each layerof an atherosclerotic plaque, while single depth measurements may beemployed to ascertain particular characteristics of the medium of alayer, be it the cap, lipid or otherwise.

Finally, it will also be appreciated that while the exemplaryembodiments disclosed herein when implemented with an extensiblefiber/guidewire and catheter arrangement are described with referenceand illustration to detecting and characterizing atheroma and/oratherosclerotic plaques, applications and implementations fordetermination of other biological constituents or analytes may beunderstood as being within the scope and breadth of the claims. Forexample, the embodiments disclosed herein may readily be adapted forinvasive or non-invasive applications including, but not limited todetection and evaluation of analytes such as glucose and glucoseconcentration.

Another important consideration is that, as a tool, particularly formedical diagnostic applications, the LCI system of the exemplaryembodiments is preferably configured to be rather small, fiber-opticbased, using non-ionizing optical radiation and when implemented with anextensible fiber/guidewire and catheter arrangement facilitatesconvenient measurements without bulky equipment and apparatus. Inaddition, the techniques described in the exemplary embodiments providefor characterization of both the tissue structure and biochemistry.Moreover, the exemplary embodiments advantageously provide real-timeresults with excellent spatial resolution (˜10 microns or better),which, for a typical broadband light source at 1,300-nm centerwavelength and 60 nm bandwidth, is approximately 10 times better thanother techniques such as intravenous ultrasound, MRI, and the like.Furthermore, unlike MRI or computerized tomography, and other imagingmethodologies, the techniques of the exemplary embodiments do notrequire expensive facilities and are relatively inexpensive tomanufacture and use. In any case, emphasis is also placed onminiaturization, portability, low power and low cost.

To facilitate appreciation of the various embodiments of the inventionreference may be made to FIG. 1, depicting an all-fiber low-coherenceinterferometer (LCI) system and the mathematical equations developedherein. Referring also to FIGS. 6, 7, 16, and 17, wherein like elementsare numbered alike, in an exemplary embodiment, an LCI systems 10, 10 bincludes, but is not limited to two optical modules: a source-detectormodule 20 a and a splitter-modulator module 40 a, and associatedprocessing systems 60. The source-detector module 20 a including, butnot limited to, a broad-band light source 22, such as a superluminescent diode (SLD) denoted hereinafter as source or SLD, attachedto a single-mode fiber 23 or waveguide, an isolator 24 configured toensure that feedback to the broad band light source 22 is maintained atless than a selected threshold. The source-detector module 20 a alsoincludes an optical detector 28.

The splitter-modulator module 40 a includes, but is not limited to, awaveguide input 41, a waveguide output 43, a splitter/coupler 50, andtwo waveguide light paths: one light path, which is denoted as thereference arm 42, has adjustable length 1 r with a reflecting device,also referred to as a mirror 46 at its end; the other light path, whichis denoted as the sensing arm 44, allows light to penetrate to adistance z in a medium/object and captures the reflected or scatteredlight from the medium. It will be appreciated that the capturedreflected or scattered light is likely to be only the so-called“ballistic photons”, i.e., those that are along the axis of thewaveguide. Provision is also made for one or more modulators 52, 54 ineach of the reference arm 42 and sensing arm 44 respectively.

Continuing with the Figures, and in particular, FIG. 17, in anotherexemplary embodiment, the source-detector module 20 b includes, but isnot limited to, a polarized broad-band light source 22, attached to asingle-mode fiber 23. The source-detector module 20 b also includes apolarizing beam splitter 25 with an quarter wave plate 26 employed toensure a selected polarization configured to facilitate ensuring thatfeedback to the broad band light source 22 is maintained at less than aselected threshold. The source-detector module 20 b also includes anoptical detector 28.

The splitter-modulator module 40 b of this embodiment includes, but isnot limited to, a waveguide inputs/output 45, a Y-splitter-combiner 51,and the two waveguide arms: reference arm 42, and sensing arm 44. Onceagain, provision is also made for one or more modulators 52, 54 in eachof the reference arm 42 and sensing arm 44 respectively.

It will be appreciated that while certain components have been describedas being in selected modules, e.g., 20, 40, such a configuration ismerely illustrative. The various components of the LCI system 10 mayreadily be distributed in one or more various modules e.g., 20, 40 assuits a given implementation or embodiment. Furthermore, in an exemplaryembodiment the waveguide arms 42, 44 and/or fibers 23 are configured forsingle-transverse-mode transmission, and preferably, but notnecessarily, polarization-maintaining waveguides or fibers. Furthermoreit will be appreciated that in any of the exemplary embodimentsdisclosed herein the waveguide and/or fiber tips of each componentjoined are configured e.g., angled-cleaved in a manner to minimizereflection at the junctions.

In order to perform the prescribed functions and desired processing, aswell as the computations therefore (e.g., the computations associatedwith detecting and utilizing the interference signal, and the like), theLCI system 10, 10 b, and more particularly, the processing system 60,may include, but is not limited to a computer system including centralprocessing unit (CPU) 62, display 64, storage 66 and the like. Thecomputer system may include, but not be limited to, a processor(s),computer(s), controller(s), memory, storage, register(s), timing,interrupt(s), communication interface(s), and input/output signalinterfaces, and the like, as well as combinations comprising at leastone of the foregoing. For example, computer system may include signalinput/output for controlling and receiving signals from thesource-detector module 20 as described herein. Additional features of acomputer system and certain processes executed therein may be disclosedat various points herein.

The processing performed throughout the LCI system 10, 10 b may bedistributed in a variety of manners as will also be described at a laterpoint herein. For example, distributing the processing performed in oneore more modules and among other processors employed. In addition,processes and data may be transmitted via a communications interface,media and the like to other processors for remote processing, additionalprocessing, storage, and database generation. Such distribution mayeliminate the need for any such component or process as described orvice versa, combining distributed processes in a various computersystems. Each of the elements described herein may have additionalfunctionality that will be described in more detail herein as well asinclude functionality and processing ancillary to the disclosedembodiments. As used herein, signal connections may physically take anyform capable of transferring a signal, including, but not limited to,electrical, optical, or radio.

The light reflected from the reference mirror 46 (Electric field E_(r))in the reference arm 42 and the light reflected or scattered from depthz within the medium or sample (Electric field E_(s)) in the sensing arm44 are combined at the optical detector 28, whose output current isproportional the combined electric fields. For example, in one instance,the output of the detector 28 is proportional to the squared magnitudeof the total electric field E_(t)=E_(r)+E_(s).

The detector current I_(d) is given by:I _(d) =η|E _(r) +E _(s)|² =I _(r) +I _(s) +i _(o)(Δl)  (1)where η is the detector quantum efficiency (typically <1),I_(r)=ηE_(r*)E_(r)* is the detector current due to E_(r) alone,I_(s)=ηE_(s*)E_(s)* is the detector current due to E_(s) alone, andthe * represents the complex conjugate. E_(r*)E_(r)* and E_(s*)E_(s)*represent the optical power in the reflected reference field andreflected sensing field, respectively. The quantity i_(o)(Δl) is theinterference or cross-correlation signal between the two optical fields,and is the signal of interest. It is given by: $\begin{matrix}{{{i_{o}\left( {\Delta\quad l} \right)} = \left. {2\sqrt{I_{r}I_{s}}} \middle| {G\left( {\Delta\quad l} \right)} \middle| {\cos\quad\phi_{s}} \right.}{{\left. {where}\quad \middle| {G\left( {\Delta\quad l} \right)} \right| = {{{\exp\left\lbrack {- \left( \frac{\Delta\quad l}{L_{c}} \right)^{2}} \right\rbrack}\quad{and}\quad\phi_{s}} = {\frac{2\pi}{\lambda_{o}}\Delta\quad l}}},}} & (2)\end{matrix}$and where λ_(o) is the center wavelength of the light source 22, Δl isthe optical path difference between the reference and sensing arms,given by:Δl=l _(r) −l _(s) where l_(s)=nz  (3)where l_(r) is the path length change in the reference arm 42, l_(s) isthe penetration of the sensing light to depth z in the sample, n is therefractive index at the location in the sample, and L_(c) is thecoherence length of the light source and, for a light source having aGaussian spectrum, it is given by: $\begin{matrix}{L_{c} = {{\frac{2\sqrt{\ln\quad 2}}{\pi}\frac{\lambda_{o}^{2}}{\Delta\lambda}} = {0.44{\frac{\lambda_{o}^{2}}{\Delta\lambda}.}}}} & (4)\end{matrix}$where Δλ is the FWHM (full width half maximum) linewidth of the lightsource 22.

It may readily be appreciated that in Equation (1), the square root termrepresents the magnitude I_(s) of the LCI signal. It is a function ofits starting depth in the sample and the reflection, transmission, andscattering properties of the sample. In particular, if the sample is ascattering material such as human tissue, theory shows I_(s) to have anexponential dependence on z, as illustrated in FIG. 2 for a skin sample.This type of profile is predicted by scattering theory in general. Thespecific profile depends on the type of medium or tissue being examined.One of the main features of LCI as applied to scattering tissues is toexperimentally obtain this profile for arbitrary tissues, whether skinfor determining features such as glucose concentration, or arterialwalls for the detection and characterization of vulnerable plaques.

A plot of the envelope (gating) function G(Δl) and of the interferencesignal G(Δl)cos φ_(s) is shown in FIGS. 3A and 3B respectively, for aninterferometer with a light source 22 having center wavelength λ_(o)=1.3μm and FWHM bandwidth Δλ=60 nm (coherence length L_(c)=12.4 μm). In FIG.3A, the detected interference signal exhibits a maximum when theinterferometer is balanced, i.e., when the path difference Δl=0. As thesystem 10 becomes increasingly unbalanced, e.g., Δl≈0, the interferencesignal exhibits maxima and minima of decreasing amplitude over a rangedetermined by Δl. The cosine term is the real interference. It undergoesmaxima and minima and has a 2π or 360 deg phase shift every time Δlchanges over a distance equal to the center wavelength of the light. Aplot of G(Δl)cos φ_(s) is shown in FIG. 3B for an interferometer withthe 1,310 nm light source.

It will be appreciated that the interference signal i_(o) exhibitssignificant amplitude only over a spatial window of approximately twicethe coherence length L_(c). As the optical bandwidth increases, thecoherence length L_(c) decreases and the spatial measurement windownarrows. The existence of this gating function highlights the ability ofLCI to resolve depth or optical path length. It means that, out of allthe possible sensing light components that are captured by orback-scattered to the sensing fiber in the interferometer, the onlycomponent that contributes to the LCI signal is that for which thereference arm length corresponds to a depth in the sample for which theinterferometer is balanced, with a resolution corresponding to thecoherence length. All other signals outside of the coherence lengthremain as parts of the dc current I_(s). As the reference arm length ischanged to a new value, the LCI signal obtained is one that correspondsto a new depth in the sample. By scanning the length of the referencearm over a given distance, then the measurement of the peak of thegating function gives the amplitude of the profile of the LCI signal asa function of depth. Thus, LCI provides a means for probing objects atprecisely defined locations within the object. Furthermore, it will beappreciated that it may be highly desirable to perform a “quick” depthscan employing larger steps in depth to identify approximately thelocations of targets of interest and then a second higher resolutionscan particularly in the areas of interest e.g. around depths where amedium change is suspected. Such an approach saves time and processingcomplexity over employing a high-resolution scan alone throughout theentire depth profile of interest.

It is noteworthy to appreciate that the phase, φ_(s), (Equations (2),(5)) of the interference signal i_(o) changes by 2π (from a maximum to aminimum then to another maximum) as Δl varies from 0 to λ_(o).Therefore, a small change in Δl results in a large phase change. It willbe further appreciated that the phase of the interference signal i_(o)is highly sensitive to small changes of optical properties of themediums, such as refractive indices, or depth z. Thus, while moderate tolarge changes may readily be observed by measuring the magnitude of theenvelope G(Δl), small changes are best detected by measuring the phaseφ_(s) of the interference signal i_(o). It will be further appreciatedthat, for certain applications, all the desired information is containedin the range from 0 to 2π. For values of Δl>λ_(o), the interferencesignal i_(o) is repetitive. Thus, in such applications, the range from 0to 2π as indicated in FIG. 3 is a range for which the desiredinformation can be measured without ambiguity. It may also be notedhowever, that if the coherence length L_(c) is short enough that theamplitude difference between the main peak and secondary peaks ismeasurable, or if a means is provided to record a particular point ofthe interference signal, then phase measurement beyond 2π may berealized by counting the fringes (the number of equivalent pointstraversed) starting from that point.

Therefore, it will readily be appreciated that there are two types ofinformation, which can be derived from the interference signal i_(o):the envelope G(Δl), or its peak G(Δl=0), which may represent scattering,reflection, and absorption; and the more sensitive changes in cos φ_(s)due to small optical property changes in the specimen under study. Inorder to make any such measurements, it is first preferable to separatethe DC components I_(r) and I_(s) from G(Δl) and cos φ_(s) in theinterferometric signal i_(o) described in Equation (5).

An LCI instrument is designed to measure the peak of the gating functionas the reference arm 42 is scanned. This is done by rectifying theinterference signal i_(o) to obtain the envelope G(Δl) and using a peakdetector the obtain the value corresponding to Δl=0, which is the peakof the LCI signal. Every type of sample exhibits its own distinct tracesignature or profile. For example, in the profile of the skin sampledepicted in FIG. 3, the portions that correspond to the stratum corneum,the epidermis, and the dermis may readily be observed. A homogeneouslyscattering sample, such as milk or a solution containing microspheres insuspension would show a uniform exponential decay as shown in FIG. 16.In FIG. 16 there is a space between the tip of the interferometer probeand the homogeneously scattering sample. In FIG. 17, the probe isimmersed in the fluid, so the signals from the probe tip and thebeginning of the scattering profile coincide.

When a medium contains several components, each component may have adifferent scattering coefficient, refractive index, and/or absorptioncoefficient. A change in the profile will occur at each interface,depending on the value of these parameters on each side of theinterface. When the two media have significantly different scatteringcharacteristics, the profile may exhibit a measurable amplitude step.FIG. 5 depicts an example of LCI profile based on observations of thewalls of arteries through flowing blood. FIG. 5A depicts an LCI profileof an arterial wall in a set-up containing blood between the probe tipand the arterial wall simulated by a sheet of rubber. The blood is ascattering medium, and the left portion of the profile is based on theblood, while the arterial wall (rubber sheet) is more highly scatteringthan the blood and therefore the profile exhibits higher relativeamplitude LCI. To the extent that enough light has penetrated throughthe blood to produce a measurable LCI for the rubber, one sees a largerLCI for the rubber, as indicated by the step in the sketch. FIG. 5Brepresents the LCI signal for a calcified plaque on an arterial wallwith a lipid pool between the plaque and the arterial wall, lookingthrough blood. In the profile depicted, the step increase due to thehigher scattering coefficient of the plaque and a step decreaseresultant from the lower scattering of the lipid pool may readily beobserved. It will be appreciated that by then measuring from thebeginning of the hump or step corresponding to the plaque to thebeginning of the portion of the signal corresponding to the lipid pool,a measure of the thickness of the plaque cap may be ascertained.

The accuracy of such a measurement is determined by the accuracy withwhich the transition can be detected. In this example, the transitionfrom the calcified plaque cap to lipid pool. Unfortunately, thetransition may not be easily detected, with sufficient accuracy, bylooking at only the amplitude of the interferometric signal i_(o).Moreover, there may be subtle changes due to some possible otherinterfaces that cannot be readily measurable from the amplitudeinformation alone. In the various exemplary embodiments describedherein, it is established that such changes may be detected from thephase information in the LCI signal. In fact, any change in materialproperty, whether it is refractive index, absorption, scattering (whichcan be treated as a change of absorption or reflection) will affect thephase of the interferometric signal i_(o). If the change is abrupt at agiven location, it will also translate into an abrupt phase shift in thesignal at that location. Such abrupt changes can occur at the boundariesbetween two regions in a sample having different optical properties:refractive index, absorption, scattering, and so on. For example, as adepth scan is conducted the phase of the interferometric signal isexpected to vary by a predictable amount for a given medium. When adifferent medium is encountered exhibiting different scatteringproperties a significant change in the properties beyond that expectedfor the previous medium will be encountered. Therefore, the thickness ofthe various layers of a vulnerable plaque may be ascertained byobserving such changes in a layered structure and recording theirpositions. In one exemplary embodiment abrupt variations in phase and orindex of refraction the order of about 0.1% per micron of scan distanceare considered as likely changes in medium.

A calculation of the high sensitivity of the phase measurement can beshown for the simple case of only a small refractive index change in thetransition from one medium (medium 1 in FIG. 5B) to another (medium 2 inFIG. 5B) over a small distance Δz. From Equation 3, the phase angleφ_(s) of the LCI signal, for a depth in the sample determined by l_(r)for an interface at depth nz (which is l_(s)) is written as:$\begin{matrix}{\phi_{s} = {{\frac{2\pi}{\lambda_{o}}\Delta\quad l} = {\frac{2\pi}{\lambda_{o}}{\left( {l_{r} - {nz}} \right).}}}} & (5)\end{matrix}$In the transition from medium 1 to medium 2, a small change in nz,represented by Δnz=nΔz+zΔn, where Δn=n₂−n₁, results in the phase change:$\begin{matrix}{{\Delta\phi}_{s} = {\frac{2\pi}{\lambda_{o}}{\left( {{n_{1}\Delta\quad z} + {z\quad\Delta\quad n}} \right).}}} & (6)\end{matrix}$

For example, consider the transition from a plaque having a refractiveindex n_(i) of 1.32 at a depth z of 50 microns to a lipid pool havingrefractive index n₂ of 1.319, over a transition distance Δz of 0.5microns. The reflection coefficient between the two regions,R=(n₂−n₁)²/(n₂+n₁)²=(0.001/2.64)²=1.43×10⁻⁷, is too small to be detectedin an amplitude measurement. However, a calculation of Δφ_(s) from thesevalues indicates a phase change of 3.43 radians or 196 degrees for thiscondition, which is large and may readily be detected. One or more ofthe exemplary embodiments disclosed herein can easily detect a phasechange of such magnitude. This approach makes it possible to observephase changes discontinuities over a small fraction of wavelength. Thus,while amplitude measurements have a resolution of the order of thecoherence length L_(c), phase measurements provide a resolution of theorder of a fraction of a wavelength λ₀. Advantageously, in applicationssuch as the detection of vulnerable plaques in human arteries, thecombination of amplitude change (when available) and phase change canthus provide resolution far exceeding that of amplitude measurementsalone. In one or more exemplary embodiments, resolutions of the order ofa fraction of a micron are achievable.

Another advantage to employing phase measurements of the LCI signal fordetection of vulnerable plaques is that this large phase change occursregardless of the amplitude of the envelope of the LCI signal, whetherthe signal is from a location near the surface of the sample or it isfrom a larger depth where the signal is much weaker due to scattering.This observation is especially significant with the study of vulnerableplaques in human arteries in the presence of blood. Scattering resultantfrom blood is significant and may reduce the optical signal strength bymore than 20 dB before it reaches the arterial walls. Additionally, thelight is further scattered by the tissues themselves. A phasemeasurement approach, permits measurement of plaque thickness with highaccuracy, even when the signal strength; is highly reduced due toscattering through blood.

Amplitude changes, in addition to the phase change can be observed whenthere are large changes in material properties as a result of reflectionand additional phase shifts. Reflection causes a fraction γ (thereflection coefficient at the boundary) of the light incident at aboundary to be reflected back to the source. In general, the reflectioncoefficient at a boundary between a first medium and a second mediumhaving complex indices n₁+ik₁ and n₂+ik₂, respectively, where n is thereal refractive index, k is the extinction coefficient and i theimaginary symbol (i²=−1) and is of the form: $\begin{matrix}{\Gamma = {\frac{\left( {n_{2} - n_{1}} \right) + {i\left( {k_{2} - k_{1}} \right)}}{\left( {n_{2} + n_{1}} \right) + {i\left( {k_{2} + k_{1}} \right)}} = {\Gamma_{m}e^{i\quad\phi_{m}}}}} & (7)\end{matrix}$

The extinction coefficient k is related to the absorption coefficient αby the relation k=αλ_(o)/2π. For the sake of this analysis, thescattering coefficient μ can be considered analogous to the absorptioncoefficient, since they affect the exponential decay of the LCI signalin similar ways. This adds a term γ_(m)E_(s)e^(iφ) ^(m) to theexpression for the electric field E at the boundary between the tworegions. Since the two media may have different scattering properties,the component of the LCI due to the scattering from the first medium maybe identified as S₁ with respect to the incident electric field E_(i) orits related optical power I_(i). Similarly, the scattering componentrelated to the second media may be identified as S₂γ, where S₂ may belarger or smaller than S₁. Unfortunately, a direct solution for theinterferometric signal is very complicated requiring a solution ofMaxwell's equations together with the scattering equations. However,advantageously, in view of the above discussion, an empiricalphenomenological approximation for the complete interferometric signalat the interface, including the scattering and absorption effects, canbe written as: $\begin{matrix}{{i_{o}\left( {\Delta\quad l} \right)} = \left. {2\sqrt{I_{r}S_{1}I_{i}}} \middle| {G\left( {\Delta\quad l} \right)} \middle| \left\lbrack {{\cos\left( {\phi_{s} + {\Delta\phi}_{s}} \right)} + {\frac{S_{2}\Gamma_{m}}{S_{1}}{\cos\left( {\phi_{s} + \phi_{m}} \right)}}} \right\rbrack \right.} & (8)\end{matrix}$Application of some algebraic manipulation facilitates reduction thissignal to the simpler formi _(o)(Δl)=2D {square root}{square root over (I _(r) S ¹ I _(i) )}|G(Δl)|cos(φ_(s)+ζ)  (9)where D is a new constant and ζ is the total phase shift. However, itshould be appreciated that this derivation is not necessary toillustrate the results. It suffices to note that for the same smallvalues of Δn discussed above and for small values of Δk (i.e., k₂−k₁),Δφ_(s), remains large at ˜196 degrees whereas both the amplitude stepS₂γ_(m)/S₁ and the extra phase component φ_(m), or ζ are negligiblysmall. However, for k₁=10 k₂ (transition from a medium with largescattering to one with low scattering, then S₂γ_(m)/S₁˜1.9 (a measurableincrease) and the additional phase shift φ_(m) is ˜36 degrees, alsomeasurable. Nevertheless, advantageously, Δφ_(s) remains the largestmeasurable change.

Various methodologies and systems have been disclosed for the detectionof the amplitude and phase information in LCI signals. For example,commonly assigned U.S. patent application Ser. No. 10/845,849, filed May14, 2004 by Alphonse discloses a method and apparatus for a method forlow coherence interferometry of a biological sample, using phase.Disclosed herein in several exemplary embodiments, there are disclosedmethodologies and systems for the detection of both the amplitude andthe phase of the LCI information for the detection of vulnerable plaque,preferably employing the phase information in the interferometricsignal. A first embodiment employs a Michelson interferometer, whileanother employs an autocorrelator, each implementation yielding similarresults.

FIG. 6 depicts system for detecting and characterizing vulnerable plaquein accordance with an exemplary embodiment. In one embodiment aMichelson interferometer similar to the interferometer of FIG. 1, isemployed, but also including a fiber-sensing probe 300 designed suchthat it can fit inside a catheter 304 to facilitate directing probinglight toward the arterial walls. Furthermore, provision is made forallowing the length of the reference arm 42 to vary as needed. One wayto change the length of the reference arm is by using a moving mirror 46such that the length of the air gap due to the mirror displacementprovides the desirable length adjustment for matching a specific depthin the sample. When the length of the adjustment desired is sufficientlysmall, the mechanical motion of a movable reflecting device 46, e.g.,mirror can be replaced by a cable fiber stretcher 91 applied to a lengthof fiber optic cable 23. In an exemplary embodiment, the cable stretcher91 may be implemented by wrapping a portion of fiber 23 in the referencearm 42 around a PZT drum 98 and applying a voltage between the inner andouter wall of the drum 98. In the case of plaque detection, displacementof 5 to 6 millimeters is sufficient to facilitate the profiling requiredto characterize plaque in a blood vessel. This displacement may readilybe achieved and scanned by applying a voltage ramp of 500-600 volts to a20-30 millimeters (mm) diameter PZT drum 98 with a few meters length offiber wound around it. For longer displacement, a longer length of fiber94 or a higher voltage can be used, up to the strain limit of the fiber,or one or more individual fiber stretchers 91 can be used in tandem.Logically, a longer, but smaller diameter drum may also be used toachieve the desired displacements based on a selected length of fiber23.

Also disclosed herein in another exemplary embodiment is another systemimplementation for detecting plaque. FIG. 7 depicts a LCI system 10 butilizing an autocorrelator in accordance with an exemplary embodiment.The autocorrelator-based LCI system 10 b includes three sections. First,an independent probe 300, which in this instance includes a fiber 23,which carries both the reference light and the sensing light. A partialmirror 46 b is employed at the tip of the fiber 23 from which part ofthe light can be reflected and part transmitted is employed. Thepartially reflected light is denoted and used as the reference light,while the light that is transmitted beyond the partial mirror 46 towardthe sample and back-scattered into the fiber 23 is denoted and used asthe sensing light. For certain applications, the ideal reflection forthe reference light from the partial mirror 46 is about 33%. However,when the sensing light is very small e.g., there is littleback-scattered light, then it is preferable to make the reflection aslow as possible, perhaps less than 1 percent, to prevent detectorsaturation by the reference light and maintain sufficient signal tonoise ratio (SNR) in the detector 28. Furthermore, this approachprevents the shot noise at the detector 28 from overpowering thedetected interference signal. In another exemplary embodiment, ratherthan employing a reference mirror 46, it may also be advantageous tocoat the fiber probe 300 tip with an anti-reflection layer and even usethe light reflected from the front surface of the object (plaque) as thereference light. It should be noted that there is a distinct delaybetween the reference and sensing light. The delay being twice thedistance the light travels beyond the fiber tip and into the sample (thedistance through blood plus the penetration depth into sample). Thisdistance is expected to be significantly larger than the coherencelength of the light source 22, and therefore the reference and objectlight cannot interfere with each other as described earlier. Thus, tocompensate for this difference a path length an interferometer sectionin this LCI system 10 b provides the correction or compensation.

Continuing with FIG. 7, the probe 300 is connected to the broadbandsource 22 by means of a circulator 25 b via an optional isolator 24. Asemployed in an exemplary embodiment, a circulator 25 b is a three-portdevice in which, light injected at one port is transmitted to a secondport, but the light reflected from the second port is deflected to athird port (similarly, an isolator together with a splitter (similar to25 of another embodiment) may also be used, but the circulator 25 b ismore efficient). The electric field of the reference light is designatedas E_(r), starting from the value E_(or) (not shown) at the reflector 46b. The field from the sensing light is designated as E_(s), and itsinitial value is E_(os) from within the sample (not shown). The totalelectric field in the probe, which is the sum of E_(r) and E_(s) isdirected to the interferometer section from the third port of thecirculator. This light serves as the input to the interferometer.

It should be appreciated that, in an embodiment using theinterferometer, as depicted in FIG. 6, it may be preferred for anexemplary embodiment to employ polarization-maintaining (PM) fiber. Inthe autocorrelator embodiment, as depicted in FIG. 7, one advantage ofhaving the reference and sensing lights in the same fiber is thatordinary single-mode (SM) fibers may be used instead of polarizationmaintaining (PM) fibers for the optical system by virtue of the factthat the relative polarization between the reference light and sensinglight is always maintained automatically. For an interferometer usingstandard SM fibers, this would not be the case because such fibers aresusceptible to polarization fluctuations caused by birefringence,handling, temperature variations, and other environmental conditions.Maintaining polarization ensures accurate interference between thereference and sensing lights.

The interferometer section of the LCI system 10 b includes two armsdenoted here 42 b and 44 b for consistency with a means to provide avariable relative delay between them. The delay may be attained bymechanical means, such as a moving reflector denoted 46 b at the end ofone arm, for example arm 42 b. A preferred means is to achieve a delayis to avoid moving apparatus associated with moving mirrors and utilizean electrically activated fiber-stretching device such as cablestretcher 91 described above. Once again, in an exemplary embodiment, astretching device 91 may be implemented by winding a length of the fiber23 in each arm 42 b, 44 b around a PZT drum 98 and applying a voltage tothe PZT drum 98. The application of a voltage of one polarity expandsthe drum, hence stresses the fiber 23 to increase its length by theamount L and provide a delay r. If a bias voltage is previously appliedto the PZT or if the fiber 23 is wound under tension, then applying thereverse polarity will have the opposite effect. By applying a voltage ofone polarity to one drum 98 and of the opposite polarity to another drum98, one can get a round trip effective path difference of 4L or a delayof 4τ. As mentioned earlier, in an exemplary embodiment, a 15-meterlength of fiber wound around a 20-30 mm PZT drum provides a length nL of5-10 mm, with the application of a peak voltage of about 500 volts in a50-millisecond ramp. For delays in the 5-20 mm range, it is acceptablefor the physical lengths of the fiber arms 42 b, 52 b to be the same andfor the desired delay to be provided only by the PZT stretchers 91,without the slower mechanical displacement. Similar to the probe, asdescribed above, when the interferometer is made from single-modefibers, it is preferable to maintain the same polarization relationshipbetween its two arms. Furthermore, to avoid the possibility ofpolarization changes upon reflection, Faraday rotator reflectors denoted46 b are used on each of the two arms 42 b and 44 b at the ends of thein the interferometer.

Considering now the operation, of interferometer portion of the LCIsystem 10 b. As depicted in the figure, the interferometer input lightE_(i)=E_(r)+E_(s) is fed to the interferometer from the circulator 23. Asplitter/coupler 50 is employed to split the input light E_(i) into twosubstantially equal components, which are transmitted to, and reflectedback from the Faraday mirrors 46 b. The returning lights denoted E_(C)and E_(D), with their respective delays are combined in splitter coupler50 and transmitted to the detector 28. Therefore, the total light inputto the detector is E_(T)=E_(C)+E_(D). Mathematical analysis of thissystem shows the usual DC terms, some cross-product terms with delaysthat are always much larger than L_(c) (the coherence length) andtherefore are vanishing and do not contribute to the interferometricsignal, and two terms which combine to give the current i_(s)(z)$\begin{matrix}{{i_{s}(z)} = {\left( {1 - R} \right)\sqrt{R}\sqrt{I_{r}{I_{s}(z)}}{\exp\left\lbrack {- \left( \frac{\Delta}{L_{c}} \right)^{2}} \right\rbrack}{\cos\left( \frac{2{\pi\Delta}}{\lambda_{o}} \right)}}} & (10)\end{matrix}$where R is the power reflection coefficient at the probe tip, and whereΔ=4 nL−2(n _(s) z)  (11)

This result is the same as for the ordinary LCI system with a Michelsoninterferometer except for the fact that Δ is double the differencebetween the scan length and the excess path length between the referencelight and sensing light. It can be seen that by adjusting L, Δ can bebrought to zero, thereby, the common optical path between the referenceand sensing signal cancels out. Thus, although the optical pathdifference between the reference and sensing lights is much larger thanthe coherence length, L_(c) the interferometer path difference Lfacilitates compensation for this difference to bring the interferencesignal under the coherence gating function. In particular, the peak ofthe signal corresponding to any depth z within the sample is obtainedwhen 2 nL=n_(s)Z. Any of the various means for adjusting an optical pathlength may be employed to adjust L, including but not limited to cablestretcher, 91 modulators e.g. 52, 54, movable reflecting devices, e.g.,46, and the like, as well as combinations including at least one of theforegoing. In fact, in an exemplary embodiment a separate cablestretcher 91 may be employed for the compensation addressed above and asecond modulator e.g., 52, 54 employed for the magnitude and phasedetection as described herein. A particular advantage of theautocorrelator configuration the LCI system 10 b over the interferometerbased LCI system 10 is that the optical circuit may be constructedemploying simple low cost SM fibers, whereas, the a Michelsoninterferometer based LCI system of FIG. 6 could require that the opticalsystem to be made out of PM fibers, particularly if the probe is to bepart of a catheter. Polarization maintaining fiber is much moreexpensive than single mode fiber.

In one or more exemplary embodiments of the invention, severalmethodologies are disclosed for extracting the pertinent informationfrom the interference signal i_(o) described in Equation (5). A firstmethodology addresses detection of the amplitude/magnitude of theenvelope of the interference signal, while others address detecting thephase, or more specifically a particular phase shift φ_(s) of theinterference signal i_(o) with respect to a depth scan. In an exemplaryembodiment the process for the measurement of the phase of the LCIsignal is applied to the detection of vulnerable plaques in a bloodvessel. Detection of plaques with the phase of the interferometricsignal includes a means to measuring phase changes and discontinuousphase change, such as occur at the interface between two media,particularly scattering media for example between blood and a fibrouscap, or between the cap and the lipid pool.

Furthermore, while the descriptions herein are further directed to thedetermination of Δl with reference to the interferometer embodiments asdepicted in FIG. 6, it should be appreciated that the methodologiesdisclosed herein are equally applicable to the autocorrelatorembodiments as depicted in FIG. 7 with Δ, as in equation (11),substituted for Δl for the purposes of the derivations. For example,from equation (5) the phase of the interferometer signal is given as${\phi_{s} = {{\frac{2\pi}{\lambda_{o}}\Delta\quad l} = {\frac{2\pi}{\lambda_{o}}\left( {l_{r} - {n_{s}z}} \right)}}},$where n_(s) is the refractive index of the sample, while for theautocorrelator, an analogous equation given as${\phi_{s} = {{\frac{2\pi}{\lambda_{o}}\Delta} = {\frac{2\pi}{\lambda_{o}}\left( {{4{nL}} - {2\left( {n_{s}z} \right)}} \right)}}},$where n is the refractive index for the fiber. Likewise, as Equation 6identifies Δφ_(s), for the interferometer, the analogous equation forthe autocorrelator would similarly be given by${\Delta\phi}_{s} = {\frac{4\pi}{\lambda_{o}}{\left( {{n_{s}\Delta\quad s} + {z\quad\Delta\quad n_{s}}} \right).}}$

In one embodiment, it may be desirable to measure sudden phase changesto facilitate locating boundaries between media. The processor 60 may beconfigured to cause the phase and/or magnitude of the interferometricsignal to be measured discretely or continuously from one target depthto another target depth. If there is no material discontinuity in theprocess, the phase shift is generally linear with scanning distance (ortime), and its slope (rate of change, first derivative) would besubstantially a constant, and the change in the slope (secondderivative) would be zero. Any material discontinuity at a given pointwould be manifested as both in a change of the slope, and in the factthat the second derivative would have a value that is different fromzero. Such a value would be positive or negative, depending on whetherthe index change is positive or negative. The process for evaluatingthese changes in phase can easily be implemented digitally by storingthe phase for each selected target depth during a depth scan and takingthe numerical first and second derivatives.

Similarly, looking to the magnitude, as mentioned earlier, if there isno material discontinuity in the process, the magnitude varies generallywith an exponential decay with scanning distance (or time). Once again,any material discontinuity at a given point would be manifested as anabrupt change in the difference and both in a change of magnitude andthereby, the slope, and in the fact in the second derivative. Theprocess for evaluating these changes in magnitude can easily beimplemented digitally by storing the magnitude for each selected targetdepth during a depth scan and taking the numerical first and secondderivatives.

It will be appreciated that there are numerous numerical methods forimplementation of a numerical derivative. As used herein the derivativemay not need to be mathematically robust, but simply an approximationthat captures the trend information of the phase of the interferometricsignal. For example, considering the phase, given by$\phi = {\frac{2\pi}{\lambda_{o}}\left( {l_{r} - {nz}} \right)}$so that in scanning from location z₁ to location z₂ within a medium ofconstant or slowly varying refractive index n, the phase changes from$\phi_{1} = {\frac{2\pi}{\lambda_{o}}\left( {l_{r} - {nz}_{1}} \right)}$to$\phi_{2} = {\frac{2\pi}{\lambda_{o}}\left( {l_{r} - {nz}_{2}} \right)}$such that its first derivative is the constant A given as:$A = {\frac{\phi_{2} - \phi_{1}}{z_{2} - z_{1}} = {\frac{2\pi}{\lambda_{o}}n\quad{{radians}/{micron}}}}$

Thus, if λ_(o)=1.3 microns and n=1.3, then A is 2 π radians/micron or360 degrees/micron. However, if during a change from z₁ to z₂ there isalso a change in refractive index, from n₁ to n₂, then the quantity A isno longer a constant. It changes from A₁ to A₂, and its rate of change,or derivative, or second derivative of the phase, is B given by:$B = {{\frac{2\pi}{\lambda_{o}}\frac{\left( {n_{2} - n_{1}} \right)}{\left( {z_{2} - z_{1}} \right)}} = {{A_{1}\frac{\left( \frac{\Delta\quad n}{n_{1}} \right)}{\Delta\quad z}{or}\frac{\Delta\quad n}{n_{1}}} = {\frac{B}{A_{1}}\Delta\quad z}}}$The threshold for measuring the abruptness of the change is the smallestvalue of B that can be measured, and is a function of the sensitivity ofthe instrument, which ultimately depends on the detection noise (e.g.,Johnson, shot, and excess intensity noises), and bandwidth in theinstrument. Thus, suppose A₁ is 360 radians/micron, and suppose that,without going to the ultimate limit of measurement capability, theinstrument is designed to measure accurately a value of B equal to 0.36degree/micron per micron. Then the abrupt index change threshold wouldbe 0.1% per micron of scan distance. It was shown in a previousapplication that the minimum measurable phase change, as determined bynoise is of the order of 10⁻⁵ radian or about 6×10⁻⁴ degrees. This wouldplace the available sensitivity at about 2×10⁻⁶ degrees per micron ofdisplacement. Finally, it will be appreciated that while the descriptionabove for an exemplary embodiment pertains to the phase shift of theinterferometric signal, an analogous approach may readily be applied forthe magnitude. Once again, while the descriptions herein are furtherdirected to the determination of Δl with reference to the interferometerembodiments as depicted in FIG. 6, it should be appreciated that themethodologies disclosed herein are equally applicable to theautocorrelator embodiments as depicted in FIG. 7 with Δ, as in equation(11), substituted for Δl for the purposes of the derivations.Magnitude Detection

Continuing now with FIGS. 1, 6, and 7, the first approach uses aperiodic ramp applied to one of the modulators 52, 54. Another approach,also called a homodyne methodology employs a sine wave applied to one ofthe modulators 52, 54. It will be appreciated that while for thepurposes of description of one or more exemplary embodiments, aparticular modulator in a particular arm of the LCI system 10 isdescribed as including a modulator, other configurations areconceivable. For example, while the description of an exemplaryembodiment calls for modulation of the length of the reference arm ofthe LCI system 10, 10 b, manipulation of other optical lengths in theLCI system 10 may be employed for establishing the interference signaland the level of modulation required to achieve the particular desiredresult.

Using one of the modulators, (m₁ 52, for example) a ramp modulation isapplied to one of the interferometer arms, the reference arm 42, forexample, changing l_(r) over a distance from −b to a over a time periodT, such that: $\begin{matrix}{{{\Delta\quad l} = {{{\frac{a}{T}t} - {b\quad{for}\quad t}} < 0 < {T\quad{and}\quad{if}\quad{periodic}}}},\quad{{\Delta\quad{l\left( {t + T} \right)}} = {\Delta\quad{{l(t)}.}}}} & (12)\end{matrix}$This yields: $\begin{matrix}{{{{G\left( {\Delta\quad l} \right)}{\cos\left( {\frac{2\pi}{\lambda_{o}}\Delta\quad l} \right)}} = {{\exp\left\lbrack {- \left( \frac{{\frac{a}{T}t} - b}{L_{c}} \right)^{2}} \right\rbrack}{\cos\left\lbrack {\frac{2\pi}{\lambda_{o}}\left( {{\frac{a}{T}t} - b} \right)} \right\rbrack}}}{{and},}} & (13) \\{{{i_{o}(t)} = {2\sqrt{I_{r}I_{s}}{\cos\left( {{2{\pi f}_{c}t} - \phi_{c}} \right)}}}{{{where}\quad f_{c}} = {{\frac{a}{\lambda_{o}T}{and}\quad\phi_{c}} = {\frac{2\pi\quad b}{\lambda_{o}}.}}}} & (14)\end{matrix}$

The resultant of the modulation represents a sine wave of frequencyf_(c) with an arbitrary phase φ_(c) determined by b, which isamplitude-modulated (AM) by the G(Δl) envelope function, now also afunction of time. FIGS. 8A and 8B depicts a plot of the function inequation (13) for a single ramp sweeping over ±2L_(c) for the lightsource example used earlier, with a=4L_(c) and b=2Lc), and for T=1.9 ms,we get f_(c)=20 KHz. When the ramp function used for modulation isperiodic, this signal repeats with the periodicity of the ramp function.Advantageously, the signal may be readily envelope-detected in similarfashion to an AM receiver signal to obtain G(Δl), and peak-detected toyield G(Δl=0), which can then be digitized for further processing.

It should be noted that it is not essential to scan over such a widerange (e.g., ±2L_(c)) in order to obtain the peak of the envelope, e.g.,G(Δl=0). Advantageously, it is sufficient to ramp over as little as justone wavelength, using a=λ_(o) and b=λ_(o)/2. The resultant signal isalmost a pure sine wave or one that is slightly amplitude-modulated byG(Δl). FIGS. 9 and 10 illustrate the response to a periodic ramp formodulator sweeps with a=5λ_(o) and for a=λ_(o) respectively, and b=a/2.FIGS. 9A and 10A depict the values of Δl, while FIGS. 9B and 10B depictthe envelope function as a function of time for the particular G(t) Δlrespectively, and FIGS. 9C and 10C depict the output current orinterference signals for each Δl, respectively.

Observation of the figures makes it evident that for a=λ_(o) there islittle need for filtering before peak detection to obtain the amplitudeas the ripples in the envelope from peak to peak are quite small. Forlarger values of a, as depicted for FIGS. 9A-9C, a simple filteringtechnique with a center frequency around f_(c) is sufficient to separatethe modulation G(Δl) [or now G(t)] from the carrier at f_(c) if desired.

In an exemplary embodiment, once the magnitude of the interferometricsignal i_(o) is ascertained, for a selected target depth z, additionalLCI signal magnitudes corresponding to other target depths are acquired.Furthermore, if desired, in order to obtain averaged distributions ofthe LCI signal intensity vs. depth multiple scans corresponding tomultiple target depths may be employed. As disclosed herein, there areseveral methodologies and exemplary LCI systems that may be employed toacquire an interferometric signal i_(o) corresponding to selecteddepths. In one exemplary embodiment, the modulator m₁ 52 may be employedto add an additional offsets denoted as Δ to the reference arm 42corresponding to a group of target depth variations Δz in the vicinityof target depth z. This approach is readily implemented employing theLCI system 10 of FIGS. 1, 6, 7, 16, and 17. It will be appreciated thatthe extent of such variations in the target depth Δz are a function ofthe geometry of the waveguide arm and modulators employed. Additionaldetails regarding the waveguide arms 42, and 44 and the configuration ofthe modulators m₁ 52 and m₂ 54 are addressed at a later point herein. Inaddition, an extension module (described at a later point herein) mayalso be implemented to facilitate variations in target depth and depthscans for some embodiments.

FIG. 11 depicts a illustrative implementation of the processes 100 thatmay be employed in accordance with an exemplary embodiment of theinvention for determination of the magnitude and/or phase of theinterference signal i_(o). The bolded portions of FIG. 11 depict animplementation of a detection scheme using the ramp modulator formagnitude determination. The optical signal is observed at the opticaldetector 28 and applied to a narrowband amplifier/filter 110 resultingin the interference signal i_(o). The interference signal is applied toa peak detector 112 to facilitate determination of the magnitude of theenvelope of the interference signal i_(o). A ramp generator 114 isutilized as the input to modulator m₁ 52 (FIGS. 1, 6, 7, 16, and 17) tofacilitate manipulation of the length of one of the arms, in thisinstance, the reference arm 42 of the LCI system 10.

Phase Detection—Ramp Modulation

As discussed earlier, the most sensitive interferometric information canbe derived from the phase variations of the interference signal i_(o)resulting from small changes in material properties. For example,referring to Equation (5), a small change Δn in the refractive index n,at a depth z in the sample, will result in a corresponding change in Δlby the amount zΔn. To analyze such a change by a ramp modulation methodas described above, the ramp described above in Equation (12), isapplied to the modulator m₁ 52, but, in addition, an extra optical pathlength zΔn is also included to facilitate addressing the phase shift inthe interference signal i_(o), yielding: $\begin{matrix}{{{\Delta\quad l} = {{\frac{a}{T}t} - b + {z\quad\Delta\quad n}}},{{{{for}\quad 0} \leqq t \leqq {T\quad{and}\quad\Delta\quad{l\left( {t + T} \right)}}} = {\Delta\quad{l(t)}}}} & (15)\end{matrix}$and writing G(Δl)˜1 for a˜λ_(o), yields: $\begin{matrix}{{{i_{o}(t)} = {2\sqrt{I_{r}I_{s}}{\cos\left( {{2\pi\quad f_{c}t} - \phi_{c} + \phi_{n}} \right)}}},{{{where}\quad\phi_{n}} = {\frac{2\pi}{\lambda_{o}}z\quad\Delta\quad{n.}}}} & (16)\end{matrix}$

The phase shift of interference signal i_(o) may readily be detectedusing a homodyne process 101 such as depicted in the block diagram ofFIG. 11, which produces output signals proportional to the sine andcosine of the phase shift to be measured. In an exemplary embodiment,the change in Δl produced by the ramp modulation generates theinterferometric signal i_(o) in the form of a sine wave,cos(ω_(c)t+φ_(c)+φ_(n)) as in Equation (16), with an additional phaseshifting component, denoted φ_(n) resulting from the change in therefractive index, Δn. At the same time, the parameter a of the rampmodulator 114 is applied to a voltage control oscillator (VCO) 120,configured to generate a sinusoidal function at a frequency ω_(c)proportional to the magnitude a from the ramp modulation. In anembodiment, a closed loop controller is employed to facilitatedetermination of φ_(n) as will be described herein. The sinusoidalfunction, cos(ω_(c)t) 122 from the VCO 120 is phase shifted with phaseangle φ, as depicted at phase shifting process 124. The phase angle φ isset to π/2, to facilitate formation of quadrature sinusoidal signals.The phase-shifted sinusoid 126 is applied to a first multiplyingdemodulator 130 configured for the loop closure and denoted as a lock-inamplifier. The sinusoidal function cos(ω_(c)t) 122 from the VCO 120(without the phase shift φ) is also applied to a second multiplyingdemodulator 132. Similar to the earlier embodiments, the interferometricsignal i_(o) from the optical detector 28 is amplified and filteredthrough a narrow band filter 110 around ω_(c), to extract the signalcos(ω_(c)t+φ_(c)+φ_(n)), which is then applied to both multipliers 130and 132 for multiplication by the sinusoidal signal 122 and the phaseshifted sinusoidal signal 126. Using the relation cos(x) cos (y)=0.5cos(x+y)+0.5 cos(x−y), it will be appreciated that the output of thefirst multiplier 130 contains a term at frequency 2ω_(c) and a DC termcos(φ_(c)+φ_(n)−φ). Advantageously, the DC term cos(φ_(c)+φ_(n)−φ) maybe readily extracted by low-pass filtering as depicted at filteringprocess 140, and becomes sin(φ_(c)+φ_(n)) if φ=π/2. Similarly, for thesecond multiplier 132, following similar low-pass filtering at process142, the dc term is cos(φ_(c)+φ_(n)). Thus, after filtering thefollowing two dc output signals are obtained:from the first modulator: I _(LP) ={square root}{square root over (I_(r) I _(s) )} sin(φ _(c)+φ_(n)) and  (17)from the lower modulator: I _(LP) ={square root}{square root over (I_(r) I _(s) )} cos(φ _(c)+φ_(n)).  (18)

It will be readily appreciated that both signals i.e., sine and cosine,contain the desired information, but the first provides bettersensitivity to small Δn changes. Preferably, both signals e.g.,Equations 17 and 18, are used with their signs being compared todetermine the quadrant in which the phase is located to properly obtainthe index change. For example, for phase shifts determined to be between0 and π/2, both signals are positive and increase or decrease inopposite manner. For phase shifts between π/2 and π, they have oppositesigns. For phase shifts between π and 3π/2, both are negative, and forphase shifts between 3π/2 and 2π, they have opposite sign.

Therefore, by measuring the two outputs and observing their signs, thephase can be unambiguously ascertained for the range from 0 to 2 π. Itis noteworthy to appreciate that this 2π limitation applies only if thevariations of G(Δl) [i.e., G(t)] are so small that the differencebetween the main peak (the absolute peak) and the adjacent ones is notreadily measurable. If that difference is measurable, then it ispossible to use the above algorithm, together with envelope detection,to ascertain the absolute peak, as well as the secondary peaks, and thusbe able to measure phase shifts much in excess of 2π without ambiguity.(see FIGS. 3A and 8A as an example).

The index of refraction change Δn can be retrieved in several ways. Onemethodology involves setting the value of b=0 (and thus φ_(c)=0) andmeasuring the values for Equations (17) or (18) directly. Anothermethodology is to adjust/manipulate the value of b, using a feedbackimplementation, to result in a change to φ_(c) until the sine functionof Equation (17) is nulled. When a null is achieved φ_(c)=−φ_(n), whichdirectly yields: $\begin{matrix}{{\Delta\quad n} = {- \frac{b}{z}}} & (19)\end{matrix}$where z is the selected target probing depth and b is the magnitude ofthe change in optical path length introduced to balance theinterferometer of the LCI system 10. For example, if the value of φ_(c)required for nulling is ascertained to be 5° (0.0873 radians) forλ_(o)=1.3 μm, it may be ascertained that (from φ=2πb/λ_(o)) the value ofb for nulling to be 0.018 μm, resulting in Δn=1.8×10⁻⁵ at z=1 mm. In oneexemplary embodiment, a voltage proportional to b is transmitted to anoptional VCO 150 to generate a sine wave of frequency proportional to b.That frequency may then be converted to a digital signal by means of anoptional zero-crossing detector 152 for further utilization or display.

The expression of Equation (19) also indicates that greater sensitivityis obtained by probing deeper into the sample. Conversely, due toscattering and absorption in the probed sample e.g., tissue, themagnitude of the returned signal (Electric field E_(s)) and thus theinterferometric signal i_(o), is reduced at greater depth in the sample.However, it is also well known that if a signal is periodic, that signalmay be retrieved by means of a high-gain narrow-bandwidth amplifier (atthe expense of measurement time). Similarly, it can be retrieved bymeans of autocorrelation, again, at the price of measurement time. Thus,it may be inferred that, by using the phase detection methodologydisclosed herein, the measurement sensitivity is, substantiallyindependent of the magnitude of the interferometric signal i_(o).

Phase Detection—Sine (Homodyne) Modulation

Turning now to another exemplary embodiment of the invention, in thiscase, the phase shift of the interference signal i_(o) is determinedutilizing a sinusoidal modulation technique. In order to detect thephase shift of the interference signal i_(o), a small sine wave signalof amplitude δ and frequency f is applied to either of the modulators 52or another modulator 54 (m₁ for example in FIG. 1 or FIG. 6 in thisinstance) for the interferometer based LCI system 10 or one of the cablestretching devices 98 of the autorcorrelator configured LCI system 10 bas depicted in FIG. 7. The small sinusoid results in a change to Δl as δcos ωt, where ω=2πf, and forms a modulation pattern on the balancedinterferometric signal such that it exhibits a “wiggle” or rides backand forth at the frequency f over the peak as shown by the heavy portionof the waveform in FIG. 12A. When the interferometer becomes unbalancedby virtue of a change in a material property, the modulation pattern(the heavy portion of the waveform) shifts resulting in the asymmetry asshown in FIG. 12B by virtue of the optical path change zΔn. Therefore,in an exemplary embodiment, for maintaining a controllable referencephase, provision is made to apply a fixed voltage to modulator m₁ 52with a fixed displacement b and resulting in a phase shift φ_(c) as inthe previous case.

Therefore, the general form of Δl at a given depth z with the sinusoidalmodulation can be written as:Δl=zΔn+b+δ cos ωt  (20)and the general form of φ_(s) is: $\begin{matrix}{\phi_{s} = {{{\frac{2\pi}{\lambda_{o}}z\quad\Delta\quad n} + {\frac{2\pi}{\lambda_{o}}b} + {\frac{2\pi}{\lambda_{o}}\delta\quad\cos\quad\omega\quad t}} = {\phi_{n} + \phi_{c} + {\phi_{\delta}\cos\quad\omega\quad t}}}} & (21)\end{matrix}$where ω=2πf and φ_(δ)=2πδ/λ_(o).Taking the cosine of the equation and converting yields:cos φ_(s)=cos(φ_(n)+φ_(c))cos(φ_(δ) cos ωt)−sin(φ_(n)+φ_(c))sin(φ_(δ)cos ωt).  (22)The resultant is a phase-modulated signal, which can be expanded intothe Fourier-Bessel series, using: $\begin{matrix}{{\cos\left( {\frac{2\pi}{\lambda_{o}}\delta\quad\cos\quad\omega\quad t} \right)} = {{J_{o}\left( {\frac{2\pi}{\lambda_{o}}\delta} \right)} + {\sum\limits_{n}{\left( {- 1} \right)^{n}2{J_{2n}\left( {\frac{2\pi}{\lambda_{o}}\delta} \right)}\cos\quad 2n\quad\omega\quad t}}}} & (23) \\{{\sin\left( {\frac{2\pi}{\lambda_{o}}\delta\quad\cos\quad\omega\quad t} \right)} = {\sum\limits_{n}{\left( {- 1} \right)^{n + 1}2{J_{{2n} - 1}\left( {\frac{2\pi}{\lambda_{o}}\delta} \right)}{\sin\left( {{2n} - 1} \right)}\omega\quad t}}} & (24)\end{matrix}$where J_(n)(x) is the Bessel function of the first kind of argument xand integer order n.

Substituting Equations (22), (23) and (24) into Equation (2) for cosφ_(s), the interferometric signal now includes a DC term J_(o), and aninfinite number of harmonics J₁, J₂, J₃, etc. of decreasing magnitude.We keep the lowest terms by filtering through a low-pass filter, afilter centered at f and one centered at 2f respectively. We obtain thefollowing outputs:I _(oo)=2{square root}{square root over (I _(r) I _(s) )} J_(o)(φ_(δ))cos(φ_(c)+φ_(n)) DC term  (25)i _(o1)(t)=4{square root}{square root over (I _(r) I _(s) )} J₁(φ_(δ))sin(φ_(c)+φ_(n))cos ωt Fundamental term  (26)i _(o2)(t)=4{square root}{square root over (I _(r) I _(s) )} J₂(φ_(δ))cos(φ_(c)+φ_(n))cos 2ωt Second harmonic term  (27)where G(Δl)≈1, since Δl<<L_(c).

It is noteworthy to appreciate that the DC term I_(oo) includes the sameinformation with respect to the argument of interest φ_(n) as the secondharmonic term i_(o2)(t) and may be employed for ascertaining φ_(n).However, it is not as stable as i₀₂(t) and is subject to drift and otherenvironmental factors. Furthermore, the DC term is not readily separablefrom the other detector DC components I_(r) and I_(s). On the otherhand, i_(o1)(t) and i_(o2)(t) are locked to the oscillator frequency,which can be controlled accurately. Therefore, it is preferred thati_(o1)(t) and i_(o2)(t) are selected as the interferometer outputs. Theamplitude of the fundamental and second harmonic terms may beascertained, by various methodologies including, but not limited to,lock-in detection, multiplication and filtering as follows:I _(o1)=2{square root}{square root over (I _(r) I _(s) )} J₁(φ_(δ))sin(φ_(c)+φ_(n))  (28)I ₀₂=2{square root}{square root over (I _(r) I _(s) )} J₂(φ_(δ))cos(φ_(c)+φ_(n)).  (29)

FIG. 13 depicts an implementation of a sinusoidal modulation anddetection or homodyne methodology shown generally as 200. Elementssimilar to earlier embodiments are similarly referenced but incrementedby one hundred. A source 210 generates a sine wave denoted cos ωt offrequency f and second one of frequency 2f locked to the first one (forexample, by means of a frequency doubler). In an exemplary embodiment afrequency f of about 100 KHz is employed, however, it will be evidentthat other frequencies may readily be utilized depending upon aparticular implementation and application of the LCI system 10 or 10 b.In fact, the frequency selected for modulation is not critical, and maybe selected in accordance with a given implementation. The frequencyselected is only limited by practical design constraints of a selectedimplementation e.g., size of components, processing requirements toimplement functions, and the like. The sine wave at frequency f is fedto modulator m₂ 54 and to the upper multiplier 230 (e.g., a lock-inamplifier), and the sine wave at frequency 2f is applied only to thelower multiplier 232. A ramp generator 214 similar to that employed inthe above embodiments, applies a dc voltage to the m₁ modulator 52 toproduce the path length bias b, which is adjustable. In an exemplaryembodiment, the path length bias b is adjusted to between 0 and λ₀ toproduce a phase shift φ_(c) between 0 and 2π. The detected interferencesignal i_(o) is amplified and passed through narrow-band filters 210 toproduce signals at ω and at 2ω, and these two signals are fed to themultipliers 230 and 232 respectively as shown. The output of themultipliers, after low-pass filtering at 240 and 242, are dc signalswhich correspond to the parameters in Equations (28) and (29).

It will be readily appreciated that except for the Bessel functioncoefficients, which are constants whose values are determined by theirarguments 2πδ/λ_(o), the functions in Equations (28) and (29) areidentical to those in Equations (17) and (18) which were obtained fromthe ramp modulation scheme described earlier. However, advantageously,sinusoidal modulation is more robust and does not need specialprecautions to generate and control the reference frequency f and theπ/2 electronic phase shift as in the previous case. In an exemplaryembodiment the selection of the operating frequency f is arbitrary.However, it is preferable to keep it above the shot noise frequencyrange, i.e., above 120 KHz, where the shot noise is not significant.

It should also be noted that δ needs not be large in order to maximizeJ₁. It will be appreciated that the maximum value of J₁(2πδ/λ_(o))occurs when (2πδ/λ_(o))=1.85, i.e., when δ=0.29λ_(o), givingJ₁(1.85)=0.582 and J₂(1.85)=0.311. Equations (28) and (29) may then beutilized in a fashion similar to that employed with Equations (17) and(18) in order to measure the phase shift due to the change in index ofrefraction φ_(n) without ambiguity between 0 to 2π.

Similarly, the value of Δn may also be obtained from the values inEquations (28) and (29), the known values of J₁, J₂, and the magnitudeof the I_(s) and I_(r) (which may be obtained via a calibration), andsetting/driving φ_(c) to zero. Also as before, in an exemplaryembodiment, an implementation employing feedback may be employed toadjust the bias b until the net phase shift is zero. Thereby, theresultant Δn=−b/z, may readily be obtained. Furthermore, using the valueof b to set the frequency of a VCO 150 and zero crossing detector 152, adigital output indicative of the value of b may be obtained tofacilitate the computation of Δn.

It should be further appreciated that the implementation depicted inFIG. 13 includes optional provisions to measure the peak of theinterferometric signal i_(o) under the application of a ramp to provideinformation on reflection and scattering coefficients. It also containsprovision to apply a signal to an optional additional modulator (such asa fiber coil around a PZT drum) to facilitate ranging measurements bymeans of extra delays applied to the reference arm 42.

Another significant aspect of an exemplary embodiment of the inventionemploying the phase of the interferometric signal is the benefitachieved in measurement of the magnitude as described above. In anotherexemplary embodiment, the while the phase is measured and feedback loopsnulled as described above, the magnitude of the interferometric signalis also measured. It should be appreciated that at the instant the addedphase φ_(c) is set/driven to zero, the magnitude is at the absolutepeak. Therefore, the phase measurement facilitates determination of themagnitude with the highest possible accuracy. Again, this approach issuperior to existing magnitude detection methods because they do notemploy the high resolution phase to control the measurement of themagnitude.

FIG. 14 represents a possible embodiment of a probe 300 for thedetection and measurement of vulnerable plaques and the way it “looks”at the wall of a blood vessel. In this particular instance, the probe300 includes one or more fibers 23 placed around a guide wire or insidea guide wire 302 within a FDA-approved catheter 304. The illustrationshows a blood vessel including a vulnerable plaque at a locationcorresponding to one of the probe elements (e.g., number 3 as indicatedin the figure).

Cross-sections for configurations for the tip of the probe 300 inaccordance with one or more exemplary embodiments are illustrated inFIG. 15. Several other configurations, such as some containing prisms,may readily be implemented as well. FIG. 15A depicts a configuration fora system that uses an interferometer as the sensing instrument e.g., LCIsystem 10. The tips of the fibers 23 are angled at about 45 degrees andthe 45-degree surface is reflection-coated to maximize the light outputtoward the wall of the blood vessel. Furthermore, the tip of the probe300 is preferably capped with an inert material such as epoxy and shapedsuch as to protect the fiber tips and prevent damage to the bloodvessel. FIG. 15B depicts a similar embodiment for use in anautocorrelator configured LCI system 10 b, where each fiber 23 elementalso includes a partial reflector 46 b as discussed earlier and theoptional extra delays 47 represented by lengths L1 and L2.

Sensitivity—Minimum Detectable Signal

Sensitivity is limited by noise, once the measurement interferometricsignal io is at or about the noise level it becomes impossible todiscern the measurement from noise. Therefore, appreciation of theimpact and contributions of noise components becomes instructive withrespect to practical considerations of measurement limitations. Thedetection of the information in Equation (28) is limited by fluctuationnoise. The minimum detectable signal is reached when it is equal to thenoise, i.e., when the signal-to-noise ratio (SNR) is equal to unity. Thenoise power is expressed in terms of the photocurrent variance σ_(i) ²,which consists of the detector noise σ_(r) ², the photon shot noiseσ_(s) ², and for the case of a broadband source 22, the excess photonnoise σ_(e) ². Hence, the total noise power is:σ_(i) ²=σ_(r) ²+σ_(s) ²+σ_(s) ²+σ_(e) ²  (30)

The SNR (for signal I_(o1) for a 1-ohm input resistance, for example),is given by: $\begin{matrix}{{{SNR} = \frac{I_{{o1}{({rms})}}^{2}}{\sigma_{i}^{2}}},{{{where}\quad I_{{o1}{({rms})}}} = \frac{I_{o1}}{\sqrt{2}}}} & (3)\end{matrix}$

The detector noise power is simply the thermal noise due to the inputresistance of the receiver. It is given by σ_(r) ²=4kTB, where k isBoltzmann's constant (k=1.38×10⁻²³ J/° K.), T is the absolutetemperature, and B is the bandwidth of the measurement. For a systemhaving 1 KHz bandwidth at room temperature (T=300° K.), its value is1.66×10⁻¹⁷ W.

The shot noise, or the noise due to the random arrivals of the photonson the detector 28 from a monochromatic source, obeys Poissonstatistics. It is given by σ_(s) ²=2eI_(dc)B, where e is the electroniccharge (1.6×10⁻¹⁹ coulombs) and I_(dc) is the average detector DCcurrent. If the total power incident on the detector 28 is of the orderof about 1 mW and the detector quantum efficiency is of the order ofunity, then I_(dc) is of the order of 1 mA, and for the same detectionbandwidth, the shot noise contribution is of the order of about3.2×10⁻¹⁹ W.

The excess intensity noise from a broadband source 22 is a Bose-Einsteinprocess. It is given by (Rollins)=σ_(e) ²=(1+V²)I_(dc) ²B/Δv, where V isthe degree of polarization of the light source 22, and Δv its frequencybandwidth. From v_(o)λ_(o)=c, where c is the speed of light in vacuum,the frequency bandwidth is given by cΔλ/λ_(o) ². For a source 22 withsingle polarization (V=0), center wavelength of 1.3 μm, FWHM wavelengthbandwidth of 60 nm (Δv=1.07×10¹³ Hz) and the same detector current andbandwidth as used previously, the excess intensity noise is about σ_(e)²=10⁻¹⁶ W.

All the noise components can be reduced by reducing the electricalbandwidth B. However, it is noteworthy to appreciate that for abroadband source, except at very low total optical power (e.g.,corresponding to detector currents below 0.1 mA), the excess intensitynoise is by far the dominant noise, followed the shot noise, thenthermal noise for a high impedance detector or receiver. Thus, formoderate optical power: $\begin{matrix}{{{SNR} \approx \frac{I_{{o1}{({rms})}}^{2}}{\sigma_{e}^{2}}},{{{where}\quad\sigma_{e}^{2}} = {I_{dc}^{2}\frac{B}{\Delta\quad v}}}} & (32)\end{matrix}$indicating for a broad band source only the excess intensity noise needbe considered to evaluate sensitivity. In addition, analysis of theexcess intensity noise permits determination of the advantages ofemploying a phase based techniques of detection/measurement of theinterferometric signal i_(o).

As an example, suppose it is desirable to determine the minimumdetectable index change at a depth z in a given specimen with the 1.3-μmlight source, 1 KHz detection bandwidth, etc. Assume I_(r)˜1 mA,I_(s)˜0.1 mA, J₁=0.582 and let Δn be small enough that the sine term inEquation (28) can be replaced by its argument. Then, for SNR=1, theresultant from Equation (32) yields:(zΔn)_(min)≈4×10⁻⁶ μm.  (33)

As mentioned earlier, the minimum detectable index change dependsinversely on the probing depth. At a depth of 1 mm, i.e., 1000 mm, theminimum index change is Δn_((min))˜4×10⁻⁹. At 2 mm probing depth thenΔn_((min))˜2×10⁻⁹. It also depends on the square root of the detectionbandwidth, so a factor of three reduction is obtained by reducing thebandwidth from 1 KHz to 100 Hz. The improvement in sensitivity of thephase measurement approach over the amplitude measurement approach stemsfrom the phase factor sin(Φ_(n)) in the expression for the phase signal,which does not exist in the amplitude case. At low signal levels, itmultiplies the amplitude signal by the factor 2πzΔn/λ_(o) in which thequantity 2πz/λ_(o) is of the order of 6,000 for the examples used in thecalculations. For example, for optical power below approximately 0.1 mWor equivalently for detector current below approximately 0.1 mA, thedominant noise source is the thermal noise. The sensitivity is obtainedin the same manner as above, but with the excess noise replaced by thethermal noise in the expression for the SNR. This changes zΔn(min)somewhat, but does not change the fact that it is a small value.

Detectable Range of Measurement Without Ambiguity

The interference signal i_(o) repeats itself after the argument of thesine function in Equation (20) changes by 2π, thus when the coherencelength L_(c) is (larger than about 10 λ_(o)) such that the maximumdetectable phase change without ambiguity is 2π, equivalent to Δl=λ_(o).This yields:(zΔn)_(max)=λ_(o)  (34)

Thus, for example, at a 1.3-μm wavelength, Δn_((max))˜1.3×10⁻³ at 1-mmprobing depth, and Δn_((max))˜6.5×10⁻⁴ at 2-mm probing depth. Just asthe probing depth can be used to control the sensitivity, it can also beused to control the maximum detectable change. The range of theinstrument is the ratio of the maximum to minimum detectable signals.For the examples discussed herein, this range is 3×10⁵ or 55 dB. For alarger index change, methodology that may be employed is to use theenvelope detection method or a combination of phase and envelopedetections as described earlier.

Note that, since these results are independent of the overall magnitudeof the interferometric signal, it is sufficient to make thesemeasurements at only one depth. The depth needs to be changed only tochange the scale of the LCI system 10.

Referring once again to FIGS. 16 and 17, broadband light sources 22including, but not limited to, SLD's are laser type structuresconfigured and designed to operate substantially without feedback, e.g.,of the order of less than 10⁻³, preferably less than 10⁻⁴, morepreferably less than 10⁻⁵. In the presence of feedback, the spectrum ofthe SLD light source 22 may be distorted, the coherence is significantlyincreased and the spectrum can exhibit very large ripples and evenlasing spikes, and thereby may become lasers. Therefore, to preventdistortion and maintain spectral integrity, low coherence, and broadbandcharacteristics, reflections back into the light source 22 are avoidedto maintain a broadband light source 22. Thus, in an exemplaryembodiment of the LCI system, isolation is provided to alleviatefeedback to the light source 22.

Continuing with FIGS. 6 and 7 as well as 16 and 17, in an exemplaryembodiment, the source-detector module 20 a, 20 b, is configured toprevent the reflected interferometer light from reaching the SLD lightsource 22 and upsetting its operation. The SLD source 22 is designed andconfigured such that it is linearly polarized. SLDs and lasers are“heterostructures”, semiconductor devices consisting of a thin “active”layer sandwiched between two “cladding” layers of lower refractiveindex, all epitaxially grown on a single crystal substrate. One suchprocess for fabrication is known as MOCVD (metalorganic chemical vapordeposition). One of the cladding layers is p-doped, and the other isn-doped. The substrate is typically n-doped, and the n-cladding layer isthe first to be deposited on it. The structure forms a p-n semiconductorjunction diode, in which the active layer is caused to emit light ofenergy equal to its bandgap upon the application of an electric current.

The structure is called heterostructure because the active and cladlayers are made of different material. This is in contrast with ordinarydiodes in which the p-n junction is formulated between similar materialsof opposite doping. The use of heterostructure has made it possible toconfine the electrical carriers to within the active region, thusproviding high efficiency and enabling operation at room temperature. Inmany heterostructures, light is emitted in both TE polarization (theelectric field in the plane of the layer) and TM polarization (electricfield perpendicular to the layer).

However, useful effects are obtained when the active layer issufficiently thin such that quantum mechanical effects become manifest.Such thin layers are called “quantum well” (QW) layers. Furthermore, theactive layer can be “strained”, i.e., a slight mismatch (of about 1%)with respect to the substrate crystal lattice can be introduced duringthe deposition of the QW layer. The strain can modify the transitioncharacteristics responsible for light emission in beneficial ways. Inparticular, the light is completely polarized in the TE mode if thestrain is compressive. Thus, it is now possible to make a linearpolarized laser or broadband SLD by compressive strain of the activelayer. In an exemplary embodiment, such a linearly polarized lightsource 22 is employed.

In one exemplary embodiment, as depicted in FIG. 16, the light from thelight source 22 is directed through an isolator 24 configured totransmit light in one direction, while blocking light in the oppositedirection. The light is directed to a splitter/coupler 50 of thesplitter-modulator module 40 a. The source-detector module 20 a alsocontains a detector 28 to receive from the splitter/coupler 50.

In another exemplary embodiment as depicted in FIG. 17, the linearlypolarized light from the SLD light source 22 is collimated with lenses27 and applied to a splitter 25. If a basic 50/50 splitter 24 isemployed, half of the returned light goes to the detector 28 and theother half is directed to the SLD light source 22. Once again, in thisconfiguration an isolator 24 may be employed to prevent feedback to thelight source 22. Similarly, as stated earlier, in another exemplaryembodiment, the splitter 25 is a polarizing beam splitter 25 operatingin cooperation with a quarter wave plate 26, employed to preventfeedback light from reaching the light source 22. The polarizing beamsplitter 25 facilitates the elimination of feedback to the SLD lightsource 22 by redirecting substantially all the reflected light from thesplitter-modulator module 40 b to the detector 28.

The splitter 25 transmits the horizontally polarized light to thequarter wave plate 26, which coverts the light to another polarization,(for example, circular polarization). Likewise, the returning,circularly polarized light is received by the quarter wave plate 26 andis reconverted to a linear polarization. However, the linearpolarization opposite, for example, vertical. The vertically polarizedlight is transmitted to the polarizing beam splitter 25, which directsall of the light to the detector 28. Advantageously, this approachtransmits substantially all of the light i.e., the interference signal,to the detector 28. Whereas embodiments employing the isolator 24transmits approximately half of the light to the detector 28.

The polarizing beam splitter 25 is a device that transmits light of onepolarization (say the horizontal, or TE-polarized SLD light) andreflects at 90° any light of the other polarization (e.g., vertical orTM-polarized). The quarter-wave plate 26 is a device that converts alinearly polarized incident light to circular polarization and convertsthe reflected circularly polarized light to a linearly polarized of theother polarization, which is then reflected at a 90° angle by thepolarizing beam splitter 25 to the detector 28. Therefore, essentiallyall the light transmitted by the light source 22 is re-polarized andtransmitted to the splitter-modulator module 40 b and all the reflectedlight from the sample and reflecting device 48 is deflected by thepolarizing beam splitter 25 to the detector 28. Advantageously, thisdoubles the light received at the detector 28 relative to the otherembodiments, and at the same time minimizes feedback to the SLD lightsource 22.

In an exemplary embodiment an SLD chip for the light source 22 hasdimensions of approximately 1 mm×0.5 mm×0.1 mm (length×width×thickness),and emits a broadband light typically of up to 50 mW upon theapplication of an electric current of the order of 200-300 mA. The lightis TE-polarized if the active layer is a compressively strained QW. TheFWHM spectrum is of the order of 2% to 3% of the central wavelengthemission. A SLD light source 22 with 1.3 μm center wavelength emissionand operating at 10 mW output power at room temperature would have abandwidth of about 40 nm and would require about 200 mA of current. Inan exemplary embodiment, for continuous wave (cw) operation at roomtemperature, the SLD light source 22 may be mounted on an optionalthermoelectric cooler (TEC) 32 a few millimeters larger than the SLDlight source 22 chip to maintain the temperature of the light source 22within its specified limits. It will be appreciated that the SLD lightsource 22 and associated TEC 32 peripherals in continuous operationwould have the largest power consumption in the LCI system 10. However,without the TEC 32, the SLD junction temperature would rise by severaldegrees under the applied current and would operate at reducedefficiency.

Advantageously, in yet another exemplary embodiment, the utilization ofa TEC 70 may readily be avoided without incurring the effects ofsignificant temperature rise by pulsed operation of the SLD light source22. Pulsed operation has the further advantage of reducing the SLDelectrical power requirement by a factor equal to the pulsing dutycycle. Moreover, for selected applications of digital technology andstorage, only a single pulse is sufficient to generate an interferencesignal and retrieve the desired information. Therefore, for example,with pulses of duration 10 μs and 1% duty factor, the LCI system 10 ofan exemplary embodiment can average 1000 measurements per second withoutcausing the temperature of the SLD light source 22 to risesignificantly. Thus, for low power consumption, the LCI system 10 shouldpreferably be designed for the SLD light source 22 to operate in apulsed mode with a low duty cycle and without a TEC 32. In such aconfiguration the source-detector module 20 would be on the order ofabout 2 centimeters (cm)×2 cm×1 cm.

The splitter-modulator module 40 a, and 40 b of an exemplary embodimentincludes a splitter/coupler 50 and Y-splitter/combiner 51 respectively,with a “reference” arm 42 and a “sensing” arm 44, the reference arm 42having a slightly longer optical path (for example, 1 to 3 mm formeasurements in biological tissues) than the sensing arm 44. The opticalpath difference between the two arms 42, 44 is configured such that theLCI system 10 balanced for the chosen probing depth z. Provision is alsomade to include a modulator m₁ 52 and m₂ 54 in the reference arm 42 andsensing arm 44 respectively.

In another exemplary embodiment, the splitter/coupler 50,Y-splitter/combiner 51 reference arm 42 and a sensing arm 44 are formedas waveguides in a substrate 53. FIG. 18 depicts an illustration of asplitter-modulator module 40 b with a Y-splitter 51 and two modulators52, 54 integrated on a LiNbO3 substrate 53. However, otherconfigurations are possible, including but not limited to separatecomponents, waveguides, optical fiber, and the like. The substrate 53for this module should preferably, but not necessarily, be selected suchthat the waveguides of the arms 42, 44 and modulators 52, 54 can befabricated on/in it by standard lithographic and evaporation techniques.In one exemplary embodiment, the waveguides of the arms 42, 44 arefabricated by thermal diffusion of titanium or other suitable metal thatincreases the index of refraction of the substrate 53, evaporatedthrough masks of appropriate width for single transverse-mode operation.In another exemplary embodiment, the waveguides are formed by annealedproton exchange in an acid bath. This process raises the refractiveindex in the diffusion region, thus creating a waveguide by virtue ofthe refractive index contrast between the diffusion region and thesurrounding regions. In an exemplary embodiment, is lithium niobate(LiNbO3) is employed as a substrate 53. It will be appreciated thatother possible materials, namely ferroelectric crystals, may be utilizedsuch as lithium tantalite (LiTaO3) and possibly indium phosphidedepending on configuration and implementation of the LCI system 10.

Lithium niobate is a ferroelectric crystal material with excellentoptical transmission characteristics over a broad wavelength range fromthe visible to the infrared. It also has a high electro-opticcoefficient, i.e., it exhibits a change of refractive index under theapplication of an external electric field. The refractive index changeis proportional to the electric field. The speed of light in atransparent solid is slower than in vacuum because of its refractiveindex. When light propagates in a waveguide built into the electro-opticmaterial, an applied electric field can alter the delay in the material,and if the electric field is time-varying, this will result in a phasemodulation of the light. The LiNbO3 material is very stable, thetechnology for making it is mature, and LiNbO3 modulators, which can becompact and are commercially available.

In an exemplary embodiment, the high electro-optic coefficient(refractive index change with applied electric field) of lithium niobateis exploited to facilitate implementation of a modulator, such asmodulators m₁ 52 and m₂ 54. In this embodiment, a modulator isimplemented on or about the waveguide arms 42, 44, by depositing metalelectrodes 56, 58 in close proximity to the waveguide arms. In oneembodiment, the metal electrodes 56, 58 are deposited on the sides ofthe waveguide arms 42, 44. In another, the metal electrodes 56, 58 maybe deposited on the waveguide arms 42, 44 with an appropriate insulationlayer, in a selected region. FIGS. 16 and 17 also shows a diagrammaticdepiction of a modulators m₁ 52, m₂ 54 in each arm 42, 44 fabricated bydepositing metal films (electrodes) 56 on the outside the waveguides anda larger “common” electrode 58 between them. Modulation with modulatorm₁ 52 is obtained by applying a voltage between the upper electrode 56and the common electrode 58, and modulation with modulator m₂ 54 isobtained by applying a voltage between the lower 56 and the commonelectrodes 58. The change of refractive index with applied voltageresults in a delay or a change of optical path between for the modulatedarm 52, 54. For a given applied voltage, the optical path change dependson the length of the electrodes 56, 58.

The process of fabricating a modulator in an exemplary embodiment isillustrated in FIGS. 19A-C. Titanium and a lithium niobate substrate 53are employed. In the diffusion process, a waveguide pattern is etched ina mask and a thin layer of titanium is vacuum-deposited onto thesubstrate 23 through the mask. The substrate 23 is then heated in anoven at about 900-1000 degrees C. to diffuse the titanium into thelithium niobate substrate 23. The index of refraction of the diffusionregion is slightly higher than that of the surrounding material, andthis constitutes waveguides in which light is guided in the diffusionregion by virtue of its higher refractive index (just as in an opticalfiber where the light propagates in the higher index core). Followingdiffusion, the metal electrodes 56 and 58 for the modulator(s) 52, 54are deposited on the sides as shown, with a small spacing d betweenthem. Application of a voltage V between one of the outer electrodes 56and the negative center electrode 58 establishes an electric field ofvalue Vld across the waveguide e.g. reference arm 42 and/or sensing arm44. In an exemplary embodiment, the width of the waveguide isapproximately 3-5 microns, and the spacing d is only a few more micronswider.

The refractive index change due to the electro-optic effect is given by$\begin{matrix}{{\Delta\quad n} = {{- \frac{1}{2}}n_{o}^{3}r\quad\frac{V}{d}}} & (35)\end{matrix}$where n_(o) is the refractive index, and r is the electro-opticcoefficient. The phase shift of a light of wavelength λ propagating in aLiNbO3 modulator is given by $\begin{matrix}{{\Delta\phi} = {\pi\quad\frac{L}{\lambda}n_{o}^{3}r\quad\frac{V}{d}}} & (36)\end{matrix}$where L is the length of the modulator electrodes 56, 58. In the contextof the LCI systems 10 disclosed herein, this corresponds to an opticalpath length change of $\begin{matrix}{{\Delta\quad l} = {\frac{1}{2}n_{o}^{3}{rL}\quad\frac{V}{d}}} & (37)\end{matrix}$

Typical material properties are:r=11.3×10⁻¹² m/Vn_(o)=2.35

To obtain larger scale modulations, it will be appreciated that anincrease in the voltage on/or the length of the modulator will result inlarger changes in the index of refraction by the modulator, resulting inan increased variation of the corresponding phase delay. For example,with a configuration of d=10 microns, an applied voltage of only 3.6volts is sufficient to yield a value of Δl or b (as discussed above) of1.3 microns (the wavelength of the light discussed in the examplesabove). This illustrates that a modulator with a range equivalent to thewavelength λ (for example) 1.3 microns may readily be achieved employingthe configuration described.

In an exemplary embodiment, the reference arm 42 is terminated in anevaporated mirror (metal or quarter-wave stack) 46, and the sensing arm44 is terminated in an anti-reflection (AR) coating, or is covered withan index-matching agent 48 that prevents or minimizes reflection fromthe end of the sensing arm 44 when placed in contact with the object tobe measured. In such a configuration splitter-modulator module 40 of anexemplary embodiment would be on the order of about 2 cm×2 cm×0.5 cm.Smaller and larger sized modules are envisioned based on the variousimplementations of the exemplary embodiments employed.

Calibration

FIG. 20 depicts an exemplary embodiment of the LCI system 10, 10 b ofFIGS. 16 and 17 with a calibration strip 70 in place. The calibrationstrip 70 can serve the dual purpose of calibration and refractive indexmatching. In an exemplary embodiment the phase associated with aselected length of the reference arm 42 is pre-calibrated to correspondto a set depth (or zero in one instance). The spot size for the light atthe tip of the sensing fiber or waveguide of the sensing arm 44 is onthe order of a few microns. The LCI system 10 may readily be calibratedby placing a strip of known parameters, e.g., refractive index (and thelike) and appropriate thickness at the sensing end of thesplitter-modulator module 40 prior to performing a measurement. Itsplacement in contact with the splitter-modulator module 40 a, 40 b(FIGS. 16 and 17) does not affect the reference arm 42, since thereference arm light does not penetrate it due to the presence of the endmirror 46. The calibration strip 70 and associated processing may beconfigured such that the LCI system 10 provides a first reading when thecalibration strip 70 is not in contact with the LCI system 10 and acorrected reading when in contact with the calibration strip.Furthermore, the calibration strip may be configured as a disposableitem.

Expansions for Ranging and Variable Depth Measurements

As describe above, some applications may require the probing depth to bedynamic to enable locating and or depth scanning. For example, inmedical diagnostics or imaging, the operator may need to probe forfeatures such as tumors, characterized by large changes of opticalproperties (absorption, reflection, or refractive index change due to adifferent density). FIGS. 21A-21C depict various adapters and severalexpansion or extension modules 90, 92, which can be attached to themodular LCI system 10, 10 b of FIGS. 16 and 17, for example, to provideadditional versatility and functionality. FIG. 21A, depicts an adapter80, configured, in one exemplary embodiment as a short section ofwaveguides 82, preferably, but not necessarily, made of the samematerial as the splitter-modulator 40 a, 40 b, with mirror 46 and ARcoating 48, which can be attached to the splitter-modulator 40 a, 40 b(with matching fluid) to operate as an interface for various extensionmodules 90, 92. The purpose of the extension module 90 is to provide foradequate lengths of the reference and sensing arms 42, 44 while using aminimum of space, and for adjusting the length of the reference arm 42and/or sensing arm 44 to enable probing at various depths for examplethe extension modules may even be employed to facilitate theinterferometer portion of the autocorrelator embodiment for the LCIsystem 10 b of FIG. 17. It should be appreciated that the length of thearms 42, 44 can be adjusted in any number of ways, includingmechanically changing an air gap between two sections of the referencearm, moving the mirror 46, actually modifying the length of the arm, andthe like, as well as combinations including at least one of theforegoing. A preferred way to manipulate the length of an arm 42, 44, inthis instance the reference arm 42, in order to maintain small size,accuracy, and stability, is to perform this operationelectromechanically.

Referring now to FIGS. 21B and 21C, in yet another exemplary embodiment,an extension modules 90 and 92 including windings of two lengths ofsingle-mode fibers 94, 96, preferably a polarization maintaining fiber(PMF), (reference and sensing arms respectively) on two drums 98 a and98 b. In one embodiment, the drum for the reference arm 42 is made outof a piezoelectric material such as, but not limited to PZT (leadzirconate titanate). The diameter of the drums 98 a, 98 b is selected tobe large enough to prevent radiation from the fibers 94, 96 due to thebending for example, about 3-4 centimeters (cm). The diameter of thefibers 94, 96 with claddings is of the order of 0.12 mm. The applicationof a voltage to the PZT drum 98 a causes it to expand or contract, thusstraining the reference fiber 94 (for example) and changing itseffective length and thereby the optical path length for the referencearm 42. Therefore, as the total length of the unstrained fiber isincreased, the total expansion increases as well. For example, if thestrain limit for the fiber 94 is about Δl/l is 10⁻⁴, then, it requires a10-meter length of fiber 94 to provide for about a 1 mm extension.Advantageously, a length tens of meters is relatively easy to achieve ifthe fiber 94 is not too lossy. In the 1.3 μm to 1.55 μm wavelengthrange, the absorption in optical fibers 94, 96 is of the order of 0.2dB/Km. There for the losses associated with a 10 meter length would bequite small. Thus, the approach of using a voltage applied apiezoelectric drum e.g., 98 a wound with a fiber 94 coil is an effectivemeans to provide changes of several millimeters in the optical pathlength of the reference arm 42.

Continuing with FIGS. 21B and 21C, the extension module 90 is configuredto provide the extension of the reference and sensing arms 42 and 44 asdescribed above and interfaces with an adapter 80 to facilitate depthprofiling. Extension module 92 also includes an evaporated metal mirror46 to terminate the reference arm 42, while the sensing arm 44 isterminated with a fiber probe 300 configured to facilitate probing suchas may include a guidewire 302 and catheter.

FIGS. 22 and 23 depict various implementations of the extendedinstrument starting from the base configuration depicted in FIGS. 16 and17 and using the adapter and the extension modules 80, 90, and 92. FIG.22 depicts a configuration of an exemplary embodiment where in additionto the source-detector module 20 a, 20 b and splitter modulator module40 a, 40 b and extension module 90 and adapter 80 are employed. Thisconfiguration facilitates probing at various depths as well asfacilitating depth profile scanning. FIG. 22 depicts a configuration ofanother exemplary embodiment where in addition to the source-detectormodule 20 and splitter modulator module 40 and extension module 92including an external probe 300 are employed. This configurationfacilitates probing either at a distance from the device or remoteinternal probing such as with a catheter and guidewire 302.

Referring now to FIG. 24, a miniaturized, optionally handheld, LCIsystem 10 is depicted in accordance with an exemplary embodiment. In anexemplary embodiment, the LCI system 10 is packaged in a small enclosure12 and includes, but is not limited to, various modules including, butnot limited to source-detector module 20 a, 20 b, splitter-modulatormodule 40 a, 40 b and may include one or more additional extension,adapter or interface modules such as 80, 90, and 92 or even calibrationstrip 70. In addition, also optionally packaged within the enclosure maybe processing system 60, including processor 62 (not shown in this view)associated controls 63 e.g., keys, selectors, pointers, and the like,display 64, data media 66, as well as communication interfaces 65, andthe like as well as rechargeable batteries. Therefore, in one exemplaryembodiment the LCI system 10 as packaged in enclosure 12 should becomparable in size to that of a Personal Digital Assistant (PDA) orsmall handheld instrument, e.g., about 8 cm×12 cm×3 cm. to readilyfacilitate handheld operation. It should be appreciated, that thepackage could be larger or smaller as needed to fit the desiredcomponent configurations.

Continuing with FIG. 24, it should also be appreciated as mentionedearlier, that various portions of the LCI system 10, and particularly,processing system 60 may be enclosed within the enclosure 12, orassociated with an external processing unit 14, or remotely located,such as with a computer processing system 60 in another facility 16. Inyet another exemplary embodiment, the LCI system 10 may also includecommunication interfaces 65, including wireless interfaces (e.g.,infrared, radio frequency, or microwave transmitter/receiver) similar tomodern computers, cell phones, PDAs, and the like to enablecommunication, including, but not limited to Internet communication,with external systems 14 and remote facilities 16. For example, asensing portion including the source-detector module 20 a, 20 b andsplitter-modulator module 40 a, 40 b can be detachable, in the formsmall handheld device, while the rest of the remainder of the LCI system10 may be in a separate package, separate computer, and the like.

The disclosed invention can be embodied in the form of computer,controller, or processor implemented processes and apparatuses forpracticing those processes. The present invention can also be embodiedin the form of computer program code containing instructions embodied intangible media 66 such as floppy diskettes, CD-ROMs, hard drives, memorychips, or any other computer-readable storage medium, wherein, when thecomputer program code is loaded into and executed by a computer,controller, or processor 62, the computer, controller, or processor 62becomes an apparatus for practicing the invention. The present inventionmay also be embodied in the form of computer program code as a datasignal 68 for example, whether stored in a storage medium, loaded intoand/or executed by a computer, controller, or processor 62 ortransmitted over some transmission medium, such as over electricalwiring or cabling, through fiber optics, or via electromagneticradiation, wherein, when the computer program code is loaded into andexecuted by a computer 62, the computer 62 becomes an apparatus forpracticing the invention. When implemented on a general-purposeprocessor the computer program code segments configure the processor tocreate specific logic circuits.

It will be appreciated that the use of first and second or other similarnomenclature for denoting similar items is not intended to specify orimply any particular order unless otherwise stated.

While the invention has been described with reference to an exemplaryembodiment, it will be understood by those skilled in the art thatvarious changes may be made and equivalents may be substituted forelements thereof without departing from the scope of the invention. Inaddition, many modifications may be made to adapt a particular situationor material to the teachings of the invention without departing from theessential scope thereof. Therefore, it is intended that the inventionnot be limited to the particular embodiment disclosed as the best modecontemplated for carrying out this invention, but that the inventionwill include all embodiments falling within the scope of the appendedclaims.

1. A method for determining a characteristic of tissue in a biologicalsample, the method comprising: directing broadband light by means of asensing light path at the biological sample at a first depth defined byeffective light path lengths of said sensing light path and a referencelight path; receiving said broadband light reflected from the biologicalsample by means of said sensing light path; directing said broadbandlight by means of said reference light path at a reflecting device;receiving said broadband light reflected from said reflecting device bymeans of said reference light path; interfering said broadband lightreflected from the biological sample and said broadband light reflectedfrom said reflecting device; detecting broadband light resulting fromsaid interfering of said broadband light reflected from the biologicalsample and said broadband light reflected from said reflecting device;determining a first phase associated with said broadband light resultingfrom said interfering of said broadband light reflected from thebiological sample and said broadband light reflected from saidreflecting device based on said first depth; varying said effectivelight path lengths of at least one of said reference light path and saidsensing light path to define a second depth; determining a second phaseassociated with said broadband light resulting from said interfering ofsaid broadband light reflected from the biological sample and saidbroadband light reflected from said reflecting device based on saidsecond depth; and determining the characteristic of the biologicalsample from said first phase and said second phase.
 2. The method ofclaim 1 wherein at least one of said reference light path and saidsensing light path includes at least one of an optical fiber and awaveguide.
 3. The method of claim 2 wherein said varying said effectivelight path lengths comprises moving said reflecting device on saidreference light path.
 4. The method of claim 2 wherein said varying saideffective light path lengths comprises modulating excitation to metallicelectrodes disposed at an optical waveguide.
 5. The method of claim 2wherein said varying said effective light path lengths comprisesmodulating excitation to a piezoelectric drum having said optical fiberwound thereon forming at least a portion of at least one of saidreference light path and said sensing light path.
 6. The method of claim1 wherein said first depth is defined by a difference between saideffective light path lengths of said reference light path and saidsensing light path.
 7. The method of claim 1 wherein said second depthis defined by a difference between said effective light path lengths ofsaid reference light path and said sensing light path.
 8. The method ofclaim 1 wherein said reflecting device is fixed.
 9. The method of claim1 wherein at least one of said determining a first phase and saiddetermining a second phase comprises: modulating said effective lightpath lengths of at least one of said reference light path and saidsensing light path in accordance with a modulator function having aphase component; and determining a magnitude of change of said effectivelight path lengths introduced by said modulating when said phasecomponent of said modulator function is generally null.
 10. The methodof claim 9 wherein said modulator function comprises a sinusoidalmodulator function.
 11. The method of claim 9 wherein said modulatorfunction comprises ramp modulator function.
 12. The method of claim 9wherein said modulating comprises modulating excitation to metallicelectrodes disposed at an optical waveguide.
 13. The method of claim 9wherein said modulating comprises modulating excitation to apiezoelectric drum having said optical fiber wound thereon forming atleast a portion of at least one of said reference light path and saidsensing light path.
 14. The method of claim 9 wherein said determining amagnitude of change of said effective light path lengths introduced bysaid modulating comprises balancing said broadband light resulting frominterference of said broadband light reflected from the biologicalsample with a feed back loop.
 15. The method of claim 1 furthercomprising calibrating at least one of said reference light path andsaid sensing light path by adjusting said effective light path lengthsof at least one of said reference light path and said sensing light pathbased on a sample exhibiting known properties.
 16. The method of claim 1wherein said determining the characteristic of the biological samplecomprises determining a difference between said first phase and saidsecond phase based on said first depth and said second depth.
 17. Themethod of claim 16 wherein said determining a difference between saidfirst phase and said second phase based on said first depth and saidsecond depth comprises: identifying the characteristic of the biologicalsample as within a medium if said difference between said first phaseand said second phase is less than about a threshold; and identifyingthe characteristic of the biological sample as a boundary betweenmediums if said difference between said first phase and said secondphase exceeds about said threshold.
 18. The method of claim 1 whereinsaid determining the characteristic of the biological sample comprisesdetermining a difference between said first phase and said second phasebased on a difference between said first depth and said second depth.19. The method of claim 18 wherein said determining a difference betweensaid first phase and said second phase based on a difference betweensaid first depth and said second depth comprises: identifying thecharacteristic of the biological sample as within a medium if a ratio ofa rate of said difference between said first phase and said second phaseand a said difference between said first depth and said second depth isless than about a threshold; and identifying the characteristic of thebiological sample as a boundary between mediums if a ratio of saiddifference between said first phase and said second phase and saiddifference between said first depth and said second depth exceeds aboutsaid threshold.
 20. The method of claim 9 further comprising determininga first variation in an index of refraction of the biological samplefrom said magnitude of change of said effective light path lengths andsaid first depth, said first variation in said index of refraction froma ratio of said magnitude of change of said effective light path lengthand said first depth.
 21. The method of claim 20 wherein said magnitudeof change of said effective light path lengths comprises one of anumerator and a denominator of said ratio and said first depth comprisesan other of said numerator and said denominator of said ratio.
 22. Themethod of claim 20 further comprising determining a second variation inan index of refraction of the biological sample from said magnitude ofchange of said effective light path lengths and said second depth, saidsecond variation in said index of refraction from a ratio of saidmagnitude of change of said effective light path length and said seconddepth.
 23. The method of claim 22 wherein said magnitude of change ofsaid effective light path lengths comprises one of a numerator and adenominator of said ratio and said second depth comprises an other ofsaid numerator and said denominator of said ratio.
 24. The method ofclaim 1 further comprising determining a first magnitude of saidbroadband light resulting from said interfering based on said firstdepth.
 25. The method of claim 24 further comprising determining asecond magnitude of said broadband light resulting from said interferingbased on said second depth.
 26. The method of claim 24 furthercomprising determining the characteristic of the biological sample fromsaid first magnitude and said second magnitude.
 27. The method of claim26 wherein said determining the characteristic of the biological samplecomprises determining a difference between said first magnitude and saidsecond magnitude based on said first depth and said second depth. 28.The method of claim 27 wherein said determining a difference betweensaid first magnitude and said second magnitude based on said first depthand said second depth comprises: identifying the characteristic of thebiological sample as within a medium if said difference between saidfirst magnitude and said second magnitude is less than about athreshold; and identifying the characteristic of the biological sampleas a boundary between mediums if said difference between said firstmagnitude and said second magnitude exceeds about said threshold. 29.The method of claim 22 wherein said determining the characteristic ofthe biological sample comprises determining a difference between saidfirst magnitude and said second magnitude based on a difference betweensaid first depth and said second depth.
 30. The method of claim 29wherein said determining a difference between said first magnitude andsaid second magnitude based on a difference between said first depth andsaid second depth comprises: identifying the characteristic of thebiological sample as within a medium if a ratio of a rate of saiddifference between said first magnitude and said second magnitude andsaid difference between said first depth and said second depth is lessthan about a threshold; and identifying the characteristic of thebiological sample as a boundary between mediums if said ratio of saidrate of said difference between said first magnitude and said secondmagnitude and said difference between said first depth and said seconddepth exceeds about said threshold.
 31. A system for determining acharacteristic of tissue in a biological sample, the system comprising:a broadband light source for providing a broadband light; a sensinglight path receptive to said broadband light from said broadband lightsource, said sensing light path configured to direct said broadbandlight at the biological sample and to receive said broadband lightreflected from the biological sample; a reflecting device; a referencelight path receptive to said broadband light from said broadband lightsource, said reference light path configured to direct said broadbandlight at said reflecting device and to receive said broadband lightreflected from said reflecting device, said reference light path coupledwith said sensing light path to facilitate interference of saidbroadband light reflected from the biological sample and said broadbandlight reflected from said fixed reflecting device; a detector receptiveto said broadband light resulting from interference of said broadbandlight reflected from the biological sample and said broadband lightreflected from said reflecting device; means for varying effective lightpath lengths of at least one of said reference light path and saidsensing light path; and a processor configured to; (1) determine a firstphase associated with said broadband light resulting from saidinterfering of said broadband light reflected from the biological sampleand said broadband light reflected from said reflecting device based ona first depth, said first depth defined by said effective light pathlengths of said sensing light path and a reference light path, (2)determine a second phase associated with said broadband light resultingfrom said interfering of said broadband light reflected from thebiological sample and said broadband light reflected from saidreflecting device based on a second depth, said second depth defined byeffective light path lengths of said sensing light path and a referencelight path, and (3) determine the characteristic of the biologicalsample from said first phase and said second phase.
 32. The system ofclaim 31 wherein at least one of said reference light path and saidsensing light path comprises at least one of an optical fiber and awaveguide.
 33. The system of claim 34 wherein said means for varyingcomprises a movable reflecting device disposed at said reference lightpath.
 34. The system of claim 32 wherein said means for varyingcomprises a modulator of metallic electrodes disposed at an opticalwaveguide.
 35. The system of claim 32 wherein said means for varyingcomprises a modulator formed with a piezoelectric drum with an opticalfiber wound thereon forming at least a portion of at least one of saidreference light path and said sensing light path.
 36. The system ofclaim 31 wherein said first depth is defined by a difference betweensaid effective light path lengths of said reference light path and saidsensing light path.
 37. The system of claim 31 wherein said second depthis defined by a difference between said effective light path lengths ofsaid reference light path and said sensing light path.
 38. The system ofclaim 31 wherein said reflecting device is fixed.
 39. The system ofclaim 32 further including a modulator associated with at least one ofsaid reference light path and said sensing light path, said modulatorfor modulating said effective light path lengths of said at least one ofsaid reference light path and said sensing light path in accordance witha modulator function having a phase component.
 40. The system of claim39 wherein said processor is further configured to determine a magnitudeof change of said effective light path length introduced by saidmodulator when said phase component of said modulator function isgenerally null for at east one of said first phase and determine saidsecond phase.
 41. The system of claim 39 wherein said modulatorcomprises a sinusoidal modulator.
 42. The system of claim 39 whereinsaid modulator comprises a ramp modulator.
 43. The system of claim 39wherein said modulator comprises metallic electrodes disposed at anoptical waveguide
 44. The system of claim 39 wherein said modulatorcomprises a piezoelectric drum with an optical fiber wound thereonforming at least a portion of at least one of said reference light pathand said sensing light path.
 45. The system of claim 39 furthercomprising a feedback loop associated with said modulator operating on alimit of said modulating such that said broadband light resulting frominterference of said broadband light reflected from the biologicalsample is balanced.
 46. The system of claim 31 further comprising acalibrating strip for calibrating at least one of said reference lightpath and said sensing light path to adjust said effective light pathlength of at least one of said reference light path and said sensinglight path based on a sample exhibiting known properties.
 47. The systemof claim 31 wherein the characteristic of the biological sample isdetermined based on a difference between said first phase and saidsecond phase and said first depth and said second depth.
 48. The systemof claim 47 wherein: the characteristic of the biological sample isidentified as within a single medium if said difference between saidfirst phase and said second phase is less than about a threshold; andthe characteristic of the biological sample is identified as a boundarybetween mediums if said difference between said first phase and saidsecond phase exceeds about said threshold.
 49. The system of claim 31wherein the characteristic of the biological sample is determined basedon a difference between said first phase and said second phase and adifference between said first depth and said second depth.
 50. Thesystem of claim 49 wherein: the characteristic of the biological sampleis identified as within a single medium if a ratio of a rate of saiddifference between said first phase and said second phase and saiddifference between said first depth and said second depth is less thanabout a threshold; and the characteristic of the biological sample isidentified as a boundary between mediums if said ratio of said rate ofsaid difference between said first phase and said second phase and saiddifference between said first depth and said second depth exceeds aboutsaid threshold.
 51. The system of claim 40 further comprising saidprocessor determines a first variation in an index of refraction of thebiological sample from said magnitude of change of said effective lightpath lengths and said first depth, said first variation in said index ofrefraction comprising ratio of said magnitude of change of saideffective light path lengths and said first depth.
 52. The system ofclaim 51 wherein said magnitude of change of said effective light pathlengths comprises one of a numerator and a denominator of said ratio andsaid first depth comprises an other of said numerator and saiddenominator of said ratio.
 53. The system of claim 51 further comprisingsaid processor determines a second variation in an index of refractionof the biological sample from said magnitude of change of said effectivelight path lengths and said second depth, said second variation in saidindex of refraction comprising a ratio of said magnitude of change ofsaid effective light path lengths and said second depth.
 54. The systemof claim 53 wherein said magnitude of change of said effective lightpath lengths comprises one of a numerator and a denominator of saidratio and said first depth comprises an other of said numerator and saiddenominator of said ratio.
 55. The system of claim 31 further comprisingsaid processor determines a first magnitude of said broadband lightresulting from said interfering based on said first depth.
 56. Thesystem of claim 55 further comprising said processor determines a secondmagnitude of said broadband light resulting from said interfering basedon said second depth.
 57. The system of claim 56 further comprising saidprocessor determines the characteristic of the biological sample fromsaid first magnitude and said second magnitude.
 58. The system of claim57 wherein the characteristic of the biological sample is determinedbased on a difference between said first magnitude and said secondmagnitude based on said first depth and said second depth.
 59. Thesystem of claim 58 wherein: the characteristic of the biological sampleis identified as within a medium if said difference between said firstmagnitude and said second magnitude is less than about a threshold; andthe characteristic of the biological sample is identified as a boundarybetween mediums if said difference between said first magnitude and saidsecond magnitude exceeds about said threshold.
 60. The system of claim56 wherein the characteristic of the biological sample is determinedbased on a difference between said first magnitude and said secondmagnitude based on a difference between said first depth and said seconddepth.
 61. The system of claim 60 wherein: the characteristic of thebiological sample is identified as within a medium if a ratio of a rateof said difference between said first magnitude and said secondmagnitude and said difference between said first depth and said seconddepth is less than about a threshold; and the characteristic of thebiological sample is identified as a boundary between mediums if saidratio of said rate of said difference between said first magnitude andsaid second magnitude and said difference between said first depth andsaid second depth exceeds about said threshold.
 62. A system fordetermining a characteristic of tissue in a biological sample, thesystem comprising: means for directing broadband light by means of asensing light path at the biological sample at a first depth defined byeffective light path lengths of said sensing light path and a referencelight path; means for receiving said broadband light reflected from thebiological sample by means of said sensing light path; means fordirecting said broadband light by means of said reference light path ata reflecting device; means for receiving said broadband light reflectedfrom said reflecting device by means of said reference light path; meansfor interfering said broadband light reflected from the biologicalsample and said broadband light reflected from said reflecting device;means for detecting broadband light resulting from said interfering ofsaid broadband light reflected from the biological sample and saidbroadband light reflected from said reflecting device; means fordetermining a first phase associated with said broadband light resultingfrom said interfering of said broadband light reflected from thebiological sample and said broadband light reflected from saidreflecting device based on said first depth; means for varying saideffective light path lengths of at least one of said reference lightpath and said sensing light path to define a second depth; means fordetermining a second phase associated with said broadband lightresulting from said interfering of said broadband light reflected fromthe biological sample and said broadband light reflected from saidreflecting device based on said second depth; and means for determiningthe characteristic of the biological sample from said first phase andsaid second phase.
 63. A storage medium encoded with a machine-readablecomputer program code for determining a characteristic of tissue in abiological sample, including instructions for causing a computer toimplement a method comprising: directing broadband light by means of asensing light path at the biological sample at a first depth defined byeffective light path lengths of said sensing light path and a referencelight path; receiving said broadband light reflected from the biologicalsample by means of said sensing light path; directing said broadbandlight by means of said reference light path at a reflecting device;receiving said broadband light reflected from said reflecting device bymeans of said reference light path; interfering said broadband lightreflected from the biological sample and said broadband light reflectedfrom said reflecting device; detecting broadband light resulting fromsaid interfering of said broadband light reflected from the biologicalsample and said broadband light reflected from said reflecting device;determining a first phase associated with said broadband light resultingfrom said interfering of said broadband light reflected from thebiological sample and said broadband light reflected from saidreflecting device based on said first depth; varying said effectivelight path lengths of at least one of said reference light path and saidsensing light path to define a second depth; determining a second phaseassociated with said broadband light resulting from said interfering ofsaid broadband light reflected from the biological sample and saidbroadband light reflected from said reflecting device based on saidsecond depth; and determining the characteristic of the biologicalsample from said first phase and said second phase.
 64. A computer datasignal embodied in a computer readable format for determining acharacteristic of tissue in a biological sample, the computer datasignal including instructions for causing a computer to implement amethod comprising: directing broadband light by means of a sensing lightpath at the biological sample at a first depth defined by effectivelight path lengths of said sensing light path and a reference lightpath; receiving said broadband light reflected from the biologicalsample by means of said sensing light path; directing said broadbandlight by means of said reference light path at a reflecting device;receiving said broadband light reflected from said reflecting device bymeans of said reference light path; interfering said broadband lightreflected from the biological sample and said broadband light reflectedfrom said reflecting device; detecting broadband light resulting fromsaid interfering of said broadband light reflected from the biologicalsample and said broadband light reflected from said reflecting device;determining a first phase associated with said broadband light resultingfrom said interfering of said broadband light reflected from thebiological sample and said broadband light reflected from saidreflecting device based on said first depth; varying said effectivelight path lengths of at least one of said reference light path and saidsensing light path to define a second depth; determining a second phaseassociated with said broadband light resulting from said interfering ofsaid broadband light reflected from the biological sample and saidbroadband light reflected from said reflecting device based on saidsecond depth; and determining the characteristic of the biologicalsample from said first phase and said second phase.